Use of compounds having ccr antagonism

ABSTRACT

It is intended to provide preventives/remedies for graft-versus-host disease and/or rejection in organ or bone marrow transplantation, rheumatoid arthritis, autoimmune diseases, allergic diseases, ischemic cerebral cell injury, myocardial infarction, chronic nephritis and arteriosclerosis. The above object can be achieved by preventives/remedies for graft-versus-host disease and/or rejection in organ or bone marrow transplantation, rheumatoid arthritis, autoimmune diseases, allergic diseases, ischemic cerebral cell injury, myocardial infarction, chronic nephritis and arteriosclerosis characterized by containing a specific compound having a CCR (CC chemokine receptor) antagonism.

TECHNICAL FIELD

The present invention relates to prophylactic and therapeutic agents forgraft-versus-host disease during organ transplantation and/or rejectionreactions, and prophylactic and therapeutic agents for rheumatoidarthritis, autoimmune disease, allergy disorders, ischemic brain celldamage, myocardial infarction, chronic nephritis, and arteriosclerosis,which contain a compound having a CC chemokine receptor (hereinafterabbreviated as CCR) antagonistic effect, and also relates to a methodfor preventing or treating these.

BACKGROUND ART

In many cases of renal disease that accompanies glomerulosclerosis, suchas IgA nephritis, diabetic nephropathy, and the like, there is a highdegree of danger that this will degenerate into renal failure, and thusnot only will the QOL of the patient decline, but their prognosis willbe poor. Hardening of the glomeruli is caused by excessive extracellularmatrix accumulation and enlargement of the mesangium region. However,prior to this point, various types of mediators, cytokines, and the likewill be discharged, and tissue remodeling will progress, due to theinfiltration of inflammatory cells such as macrophages and the like.When this occurs, groups of molecules referred to as chemokines willactivate cells involved in inflammation such as macrophages and the likevia chemokine receptors (see for example Non-Patent Document 1). Thus,the present inventors surmised that if the effects of chemokines areinhibited by administering a chemokine antagonist compound, the impactof inflammatory cells such as macrophages and the like onglomerulosclerosis can be controlled. Conventionally, ACE inhibitors andAT1 inhibitors are employed in treatments aimed at controlling renalfibrosis, but are not prescribed to patients whose disease hasprogressed due to the possibility that changes in hemodynamics will havean adverse impact on renal function. The development of a fibrosisinhibitor that will not have an impact on hemodynamics is desired.Recently, a relation has been reported between a gene polymorph of CCR5(one type of chemokine receptor) and the rate at which renal disordersoccur in Type 2 diabetics (see for example Non-Patent Document 2). Inaddition, AOP-RANTES (a CCR5 antagonist) will control fibrosis inexperimental glomerulonephritis models (see for example Non-PatentDocument 3). From these findings, the present inventors surmise thatrenal disorders can be controlled if chemokine receptors are blocked.However, there have been no reports of a low molecular weight chemokineantagonist compound that will control renal disorders such asglomerulonephritis and the like.

With ischemic cerebrovascular disease represented by cerebralinfarction, it is thought that cerebral tissue damage and cerebralfunction damage caused by a decline in cerebral blood flow due toconstriction, blockage, or a decline in perfusion pressure of cerebralblood vessels, metabolic disturbances in brain energy due to ahyperacute decline in cerebral blood flow, abnormal isolation ofglutamic acid due to cell membrane depolarization, activation of varioustypes of enzymes (protease, lipase, and others) due to an increase inintracellular calcium, an increase in various types of active oxygen,and the like, play a role therein.

Drugs that are used to treat this include thrombolytic agents (tPA) thatare targeted at dissolving blood clots, and antiplatelet andanticoagulant drugs that are targeted at preventing the enlargement andreoccurrence of blood clots. However, the anticipated effects have notbeen observed because, among other things, some effects have not beenclear, and there have been extremely few patients to whom these havebeen administered in a limited treatment period.

In addition, toward the goal of protecting cerebral tissue by stoppingthe damage cascade, drugs having various mechanisms of action such asglutamic acid antagonists, calcium antagonists, and antioxidants, havebeen developed as therapeutic agents for acute stage cerebralinfarction. Because of that, effective cerebral protection drugs areearnestly desired. From the viewpoint of the temporal treatment stage,the possibility of cerebral protection drugs targeted at inflammatoryreactions that are elicited by primary cerebral tissue damage, andthought to be related to increases in tissue damage is suggested (seefor example Non-Patent Document 4).

An increase in various types of inflammatory cytokines at the point ofdamage due to cerebral ischemia has been confirmed (see for exampleNon-Patent Documents 5 and 6). These are thought to have an effect onthe enlargement and progression of cerebral tissue damage, and thusantagonists of the receptors (CCR, CXCR, CR, CX3CR) that these cytokinesact upon are expected to control the enlargement of ischemic cerebraldamage that is represented by cerebral infarction (see for exampleNon-Patent Document 7). In addition, the same enlargement of cerebraltissue damage is seen in other cerebrovascular accidents (cerebralhemorrhage, subarachnoid hemorrhage, and the like), head trauma, and inAlzheimer's disease, multiple sclerosis (MS), AIDS encephalopathy, andthe like that are thought to be related to the progression ofintracerebral inflammation reactions, and thus these antagonists arealso thought to be effective in the progression and enlargement of thesecentral nervous system degenerative diseases. From these findings, thepresent inventors surmise that these cerebrovascular accidents and headtrauma can be controlled if chemokine receptors are blocked. However, ithas not been confirmed that compounds having a CCR antagonistic effectare effective in the treatment of these cerebrovascular accidents andhead trauma.

Osteoarthritis is a chronic progressive disease that is based upon thedeterioration of joint cartilage. In osteoarthritis, the cartilagematrix is destroyed by such things as ageing, excessive dynamic load,and inflammation, and the flexibility and elasticity of the cartilagewill be lost to thus produce impairment to joint function. In thetreatment of osteoarthritis, it is important to stop or slow cartilagedamage. However at present, the drugs that are clinically used againstosteoarthritis only treat the symptoms thereof, such as pain andanti-inflammatory agents (steroids, non-steroidal anti-inflammatorydrugs), and joint cartilage protective drugs (hyaluronic acidpreparations). Thus, drugs that will improve the structural degenerationof joint cartilage are desired as therapeutic agents.

Cartilage damage is caused by the breakdown of the proteoglycan and TypeII collagen in the cartilage matrix. The cells that are associated withcartilage damage include the chondrocytes and synoviocytes that form thejoints. These cells will increase production of enzymes such asaggrecanase and matrix metalloproteinase due to the stimulation ofinflammatory cytokines such as interleukin-I (IL-1), and these enzymeswill immediately break down the cartilage matrix. It is thought thatthis is the target of a cartilage damage inhibitor in this series ofprocesses. With regard to the connection between osteoarthritis andchemokines, it has been reported that the production of variouschemokines by chondrocytes and synoviocytes has been observed inosteoarthritis patients, and that this production is powerfully promotedby the stimulation of the inflammatory cytokines (see for exampleNon-Patent Documents 8 and 9). In fact, high levels of chemokines havebeen detected in the synovial fluid of osteoarthritis patients (see forexample Non-Patent Document 10). More recently, it has been made clearthat chemokine receptors are present in both chondrocytes andsynoviocytes, specific chemokines will stimulate the production ofcytokines and matrix metalloproteinase via these receptors, and thatthis will induce cartilage damage (see for example Non-Patent Documents11 and 12), and this suggests that chemokines play an intimate roll inthe progress of osteoarthritis. Thus, the present inventors surmisedthat if the bonding of chemokines to chondrocytes and synoviocytes canbe prevented by administering a chemokine antagonist compound, thecartilage damage of osteoarthritis can be controlled. However, therehave still been no reports of a low molecular weight chemokineantagonist compound that will control the cartilage damage ofosteoarthritis.

With rheumatoid arthritis, the infiltration of inflammatory cells fromthe microvasculature of the synovial membrane will first occur, and thenwill progress to chronic inflammation and synoviocyte tylosis. Varioustypes of chemokines will play a role in the infiltration of cells intothe joint. With rheumatoid arthritis, the manifestation of CXCchemokines such as IL-8 and GRO, and CC chemokines such as RANTES,MIP-1α, MIP-1β, and MCP-1, is accelerated. These are produced byinfiltrating cells and the abnormal growth of synoviocytes. In the sameway, the inflammatory cytokines such as TNF-α whose production isaccelerated in rheumatoid arthritis will strongly induce the productionof chemokines from these cells. The chemokines will affect the cellshaving the respective receptors that have infiltrated in large numbersinside the joint, and will further accelerate the infiltration ofinflammatory cells. Conventionally, compounds such as methotrexate andthe like are used to control the growth of these types of infiltratingcells and the abnormal growth of synoviocytes, and anti-TNF-α treatmentmethods with biological preparations are performed in order to controlthe accelerated expression of chemokines. However, the former havestrong side effects, and the latter has the problem of high cost, andthus a drug having weak side effects and which can be supplied moreinexpensively is desired.

Recently, it has been reported that joint inflammation can be controlledin animal models of rheumatoid arthritis by the administration ofan-anti-chemokine antibody (see for example Non-Patent Document 13) or achemokine analog (see for example Non-Patent Document 14). In addition,it has been reported that the chronic rheumatoid arthritis incident rateof Caucasians that do not express CCR5 (CCR5Δ32) (one type of chemokinereceptor) in immunocytes that are missing 32 base pairs in the CCR5 geneis significantly lower than those having the wild type CCR5 gene (seefor example Non-Patent Document 15), and thus suggests that chemokinesplay an intimate role in chronic rheumatoid arthritis. From thesefindings, the present inventors surmise that chronic rheumatoidarthritis can be controlled if chemokine receptors are blocked. However,there are no reports of chemokine antagonist compounds that will controlchronic rheumatoid arthritis.

Because atherosclerosis is an important risk factor for the occurrenceof cardiovascular events, controlling the occurrence of atherosclerosisis thought to be important in the control of cardiovascular events. Upuntil now, it has been reported that therapeutic agents for hyperlipemiasuch as statins and the like will improve atherosclerosis, and thus therate of occurrence of cardiovascular events will improve. However, therate of effectiveness of these is approximately 30% (see for exampleNon-Patent Document 16), and thus drugs having another mechanism ofaction are desired.

The infiltration and activation of monocytes in the vascular wall is theinitial step in atherosclerosis, and the monocytes are the primaryconstituent of unstable plaque that will easily give rise to furtherruptures (see for example Non-Patent Documents 17 and 18). MCP-1 is onetype of the CC chemokine family, and exhibits strong chemotaxis via CCR2receptors (see for example Non-Patent Document 19). It has been reportedthat the occurrence of atherosclerosis in ApoE and CCR2 double knock-outmice will be controlled in comparison with ApoE knock-out mice (see forexample Non-Patent Document 20). From these findings, the presentinventors surmise that atherosclerosis can be controlled if chemokinereceptors such as CCR2 are blocked. However, there are no reportedexamples in which the prevention and treatment of atherosclerosis bymeans of the administration of a compound having a chemokine receptorantagonist effect has been confirmed.

Transplant damage caused by humoral antibodies and macrophages plays arole in graft reactions, but generally speaking, graft rejection areprimarily caused by histocompatibility antigens expressed by thetransplanted cells being recognized as non-self, and activated T cellsgrown by the host infiltrating, accumulating in, and attacking thetransplant. The infiltration of T cells into the transplant location isinduced by a plurality of chemokines that are produced at graft locationbinding to chemokine receptors on the T cell surface. Thus, the presentinventors surmise that if the binding of the chemokines to the T cellsis prevented by administering a chemokine antagonist compound, therejection can be controlled by inhibiting the infiltration of T cells tothe transplant. Conventionally, drugs such as cyclosporin and tacrolimusare widely used in clinical settings to control rejection. However,there are problems with this such as a low organ take ratio and strongside effects, and thus a drug is desired in which a higher take ratiocan be expected and which has weak side effects.

Recently, the long term graft survival of transplanted organs in atransplant model that employed a mouse in which a specific chemokinereceptor was knocked out has been reported (see for example Non-PatentDocument 21), as well as the control of rejection in an animal model towhich a chemokine antagonist (see for example Non-Patent Document 21) ora chemokine analog (see for example Non-Patent. Document 22) wasadministered. In addition, it has been reported that the graft survivalratio of Caucasian kidney transplant patients that do not express CCR5(CCR5Δ32) (one type of chemokine receptor) in immunocytes that aremissing 32 base pairs in the CCR5 gene is significantly higher thanthose having the wild type CCR5 gene (see for example Non-PatentDocument 23), and thus suggests that chemokines play an intimate role inrejection. However, there are no reports of chemokine antagonistcompounds that will control graft rejection.

It is known that the concentration of MCP-1, MIP-1, RANTES, and othersbelonging to the chemokine family will increase in the blood of acutemyocardial infarction patients, and that this correlates with the degreeof seriousness of the disease, and thus it is thought that thesechemokines play an intimate role in the occurrence and progress of acutemyocardial infarction. In addition, because an increase in theexpression of CCR1, CCR2 and other chemokine receptors has beenidentified in end-stage cardiac insufficiency, and because theexpression of CCR5 is confirmed in coronary artery atherosclerosis, itis thought that there is a connection between these chemokine receptorsand things such as cardiac insufficiency and coronary artery disease.From these findings, the present inventors surmise that the occurrenceand progression of acute myocardial infarction can be controlled ifchemokine receptors are blocked. However, there are no reports of theeffects of chemokine antagonist agents in the prevention and treatmentof that cardiovascular disease.

Various types of benzazepine compounds (see for example Patent Documents1, 2, 3, 4 and 5) and various types of piperidine compounds (see forexample Patent Documents 7 and 8) are known as compounds having a CCRantagonist effect and particularly a CCR5 antagonist effect. However,these compounds have been primarily disclosed as therapeutic agents forHIV infection, and have not at all been disclosed with regard to thingssuch as the prevention and treatment of graft-versus-host disease and/orrejection during organ transplantation, and the prevention and treatmentof chronic rheumatoid arthritis, autoimmune diseases, allergicdisorders, ischemic brain cell damage, myocardial infarction, chronicnephritis, and arteriosclerosis.

In addition, compounds having a specific chemical structure and achemokine receptor antagonist effect are known to be effective withrespect to inflammation, immunodeficiency, asthma, allergic disorders(see for example Patent Document 9), immunodeficiency (see for examplePatent Document 10), cardiac insufficiency, inflammation, allergicdisorders, dermatitis, conjunctivitis, atherosclerosis, and rheumatoidarthritis (see for example Patent Documents 11 and 12), graft rejection,inflammatory bowel disease, rheumatoid arthritis, and multiple sclerosis(see for example Patent Documents 13 and 14), AIDS, inflammation,immunoregulatory insufficiency, asthma, allergic rheumatism, dermatitis,conjunctivitis, arteriosclerosis, and rheumatoid arthritis (see forexample Patent Documents 15, 16, 17, and 18), AIDS, chronic rheumatoidarthritis, nephritis, post-transplant rejection graft-versus-hostdisease, diabetes, chronic obstructive pulmonary disease, bronchialasthma, atopic dermatitis, sarcoidosis, fibrosis, pulmonary arteryatherosclerosis, and psoriatic inflammatory bowel disease (see forexample Patent Document 19), asthma, atopic dermatitis, rheumatoidarthritis, sarcoidosis, parapulmonary fibrosis, arteriosclerosis,psoriasis, multiple sclerosis, post-transplant rejection reactions, andinflammatory bowel disease (see for example Patent Document 20).However, these are no more than the compounds having these specificchemical structures that are known.

Prior art documents relating to the invention of this application are asfollows.

Non-Patent Document 1:

-   J Am Soc Nephrol, 2000, Vol. 11, 152    Non-Patent Document 2:-   Diabetes, 2002, Vol. 51, p. 238    Non-Patent Document 3:-   Kidney Int, 1999, Vol. 56, p. 2107    Non-Patent Document 4:-   J Cereb Blood Flow Metab. 21, 683-689 (2001)    Non-Patent Document 5:-   J Neuroimmunol. 56, 127-134 (1995)    Non-Patent Document 6:-   Neurosci Lett. 227, 173-176 (1997)    Non-Patent Document 7:-   J Cereb Blood Flow Metab. 21, 1430-1435 (2001)    Non-Patent Document 8:-   J Rheumatol, 1999, Vol. 26, p. 1992    Non-Patent Document 9:-   J Immunol, 1994, Vol. 152, p. 2060    Non-Patent Document 10:-   Clin Immunol Immunopathol, 1995, Vol. 77, p. 307    Non-Patent Document 11:-   Arthritis Rheum, 2001, Vol. 44, p. 1633    Non-Patent Document 12:-   J Immunol, 2001, Vol. 167, p. 5381)    Non-Patent Document 13:-   J. Clin. Invest. 1998, Vol 101, p. 2910)    Non-Patent Document 14:-   Immunol. Lett., 1997, Vol 57, p. 117)    Non-Patent Document 15:-   Arthritis Rheum., 1999, Vol. 42, p. 989)    Non-Patent Document 16:-   Lancet, 1994, vol. 344, p. 1383)    Non-Patent Document 17:-   N Eng J Med, 1999, Vol. 340, p. 115)    Non-Patent Document 18:-   Circulation, 1998, vol. 97, p. 75)    Non-Patent Document 19:-   Blood, 1997, vol. 90, p. 909)    Non-Patent Document 20:-   Nature, 1998, vol. 394, p. 894)    Non-Patent Document 21:-   Transplantation, 2001, Vol. 72, p. 1195)    Non-Patent Document 22:-   FASEB, 1999, Vol. 13, p. 1371)    Non-Patent Document 23:-   Lancet, 2001, Vol. 357, p. 1758)    Patent Publication 1:-   WO 99/32100    Patent Publication 2:-   WO 00/10965    Patent Publication 3:-   WO 00/37455    Patent Publication 4:-   WO 00/68203    Patent Publication 5:-   WO 00/76993    Patent Publication 6:-   WO 00/66551    Patent Publication 7:-   WO 01/25200    Patent Publication 8:-   WO 01/25199    Patent Publication 9:-   WO 98/27815    Patent Publication 10:-   WO 00/56729    Patent Publication 11:-   WO 00/59497    Patent Publication 12:-   WO 00/59498    Patent Publication 13:-   WO 00/66558    Patent Publication 14:-   WO 00/66559    Patent Publication 15:-   WO 00/76511    Patent Publication 16:-   WO 00/76512    Patent Publication 17:-   WO 00/76514    Patent Publication 18:-   WO 00/76973    Patent Publication 19:-   WO 01/42208    Patent Publication 20:-   WO 01/64213

DISCLOSURE OF THE INVENTION

As a result of various studies of compounds having a CCR antagonisteffect, the present inventors found specific compounds having a CCRantagonistic effect that are effective in the prevention and treatmentof graft-versus-host disease and rejection reactions during organtransplantation, and also effective in the prevention and treatment ofrheumatoid arthritis, autoimmune diseases, allergic disorders, ischemicbrain cell damage, myocardial infarction, chronic nephritis, andarteriosclerosis, and completed the present invention. In other words,the present invention provides agents that prevent and treat thesediseases.

The present invention relates to:

-   -   (1) An agent for the prevention or treatment of graft-versus        host disease and/or rejection reactions during organ or bone        marrow transplantation which comprises a compound having a CCR        antagonistic effect represented by the formula:        wherein R^(a1) is a hydrogen atom, a hydrocarbon group which may        be substituted, a non-aromatic heterocyclic group which may be        substituted, R^(a2) is a hydrocarbon group which may be        substituted, a non-aromatic heterocyclic group which may be        substituted, or R^(a1) and R^(a2) may combine with each other        together with A^(a) to form a heterocyclic group which may be        substituted, A^(a) is N or N⁺—R^(a5).Y^(a−) (R^(a5) is a        hydrocarbon group, Y^(a−) is a counter anion), R^(a3) is a        cyclic hydrocarbon group which may be substituted or a        heterocyclic group which may be substituted, na is 0 or 1,        R^(a4) is a hydrogen atom, a hydrocarbon group which may be        substituted, a heterocyclic group which may be substituted, an        alkoxy group which may be substituted, an aryloxy group which        may be substituted, or an amino group which may be substituted,        E^(a) is a divalent aliphatic hydrocarbon group which may be        substituted by a group other than an oxo group, G^(a1) is a        bond, CO or SO₂, G^(a2) is CO, SO₂, NHCO, CONH or OCO, J^(a) is        methine or a nitrogen atom, and each of Q^(a) and R^(a) is a        bond or a divalent C₁₋₃ aliphatic hydrocarbon which may be        substituted, with the proviso that J^(a) is methine when G^(a2)        is OCO, one of Q^(a) and R^(a) is not a bond when the other is a        bond, and each of Q^(a) and R^(a) is not substituted by an oxo        group when G^(a1) is a bond,        the formula:        wherein R^(b1) is a hydrocarbon group which may be substituted;        R^(b2) is a cyclic hydrocarbon group which may be substituted or        a heterocyclic group which may be substituted; R^(b3) is a        halogen atom, a carbamoyl group which may be substituted, a        sulfamoyl group which may be substituted, an acyl group derived        from a sulfonic acid, a C₁₋₄ alkyl group which may be        substituted, a C₁₋₄ alkoxy group which may be substituted, an        amino group which may be substituted, a nitro group or a cyano        group; R^(b4) is a hydrogen atom or a hydroxy group; nb is an        integer of 0 or 1; pb is an integer of 0 or 1 to 4,        the formula:        wherein R^(c1) is a hydrocarbon group, R^(c2) is a hydrocarbon        group having 2 or more carbon atoms, or R^(c1) and R^(c2) may be        bound together with the adjacent nitrogen atom to form a ring        which may have a substituent or substituents, R^(c3) is a        hydrocarbon group which may have a substituent or substituents        or a heterocyclic group which may have a substituent or        substituents, R^(c4) is a hydrogen atom, a hydrocarbon group        which may have a substituent or substituents or a heterocyclic        group which may have a substituent or substituents, E^(c) is a        divalent aliphatic hydrocarbon group which may have a        substituent or substituents other than an oxo group, G^(c) is CO        or SO₂, J^(c) is a nitrogen atom or a methine group which may        have a substituent or substituents, and Q^(c) and R^(c) are each        a bond or a divalent aliphatic C₁₋₃ hydrocarbon group which may        have a substituent or substituents,        the formula:        wherein A^(d) is a group represented by the formula:        wherein, R^(d3) is (1) a hydrocarbon group which may be        substituted, (2) a C₁₋₄ alkoxy group which may be substituted        or (3) an amino group which may be substituted; X^(d) is a bond,        —SO₂— or —CO—; nd is an integer of 1 to 3; md is 0 or an integer        of 1 to 3; R^(d4) and R^(d5) are the same or different and each        of which is a hydrogen atom or a C₁₋₆ alkyl group; R^(d6) is a        hydroxyl group, a C₁₋₆ alkyl group or a C₂₋₆ alkenyl group; rd        is an integer of 2 to 4; B^(d) is a bond, —CH₂—, —SO₂—, —SO—,        —S—, —O—, —CO—, —NR^(da)—SO₂— or —NR^(da)—CO— (wherein, R^(da)        is a hydrogen atom, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group or        a C₃₋₈ cycloalkyl group); each of pd and qd is 0 or an integer        of 1 to 4; R^(d1) is a halogen atom, a C₁₋₆ alkyl group, a C₂₋₄        alkenyl group, a C₁₋₄ alkanoyl group, a C₁₋₄ alkoxy group, a        cyano group, a trifloromethyl group, a nitro group, a hydroxyl        group, an amino group or an amidino group; R^(d2) is 1) a        halogen, 2) a C₁₋₆ alkyl which may be substituted by a halogen        or a C₁₋₄ alkoxy, 3) a C₁₋₄ alkoxy which may be substituted by a        halogen or a C₁₋₄ alkoxy, 4) nitro, 5) cyano, 6) hydroxyl, 7) a        C₁₋₄ alkanoylamino, 8) SO₂NR^(db)R^(dc), 9) SO₂R^(dd), 10)        CONR^(db)R^(dc), 11) NR^(db)R^(dc) or 12) NR^(da)—SO₂R^(dd)        (wherein, R^(da) has the meaning given above, and R^(db) and        R^(dc) may be the same or different, and are (1) a hydrogen        atom, (2) a C₁₋₆ alkyl group which may be substituted by a        halogen or a C₁₋₄ alkoxy, or (3) a C₃₋₈ cycloalkyl group which        may be substituted by a halogen or a C₁₋₄ alkoxy, or R^(db) and        R^(dc) may bond with a nitrogen atom to form a cyclic amino        group and R^(dd) is a C₁₋₆ alkyl group or a C₃₋₈ cycloalkyl        group), each R^(d1) may be the same or different from each other        when pd is two or more, and each R^(d2), may be the same or        different from each other when qd is two or more, or        the formula:        R^(e1)—X^(e1)—W^(e)—X^(e2)-Z^(e1)-Z^(e2)—R^(e2)  (eI)        wherein R^(e1) represents a 5 to 6-membered cyclic ring group        which may be substituted, X^(e1) represents a bond or a bivalent        group, in which the number of atoms constituting the        straight-chain portion is 1 to 4, W^(e) represents a bivalent        group represented by formula:        wherein each of ring A^(e) and ring B^(e) represents a 5- to        7-membered cyclic group which may be substituted, each of Ee₁        and Ee₄ is a carbon atom which may be substituted or a nitrogen        atom which may be substituted, each of Ee₂ and Ee₃ is a carbon        atom which may be substituted, a nitrogen atom which may be        substituted, or a sulfur atom which may be oxidized or an oxygen        atom, each of ae and be is a single bond or a double bond),        X^(e2) is a bivalent group in which the number of atoms        constituting the straight-chain portion is 1 to 4, Z^(e1) is a        bond or a bivalent cyclic ring group, Z^(e2) is a bond or a        bivalent cyclic ring group in which the number of atoms        constituting the straight-chain portion is 1 to 4, and R^(e2)        is (1) an amino group which may be substituted, and the nitrogen        atom may be converted into a quaternary ammonium or an        N-oxide, (2) a nitrogen-containing heterocyclic ring group which        may be substituted, may contain sulfur atom or an oxygen atom as        a ring-constituting atom, and the nitrogen atom may be converted        into a quaternary ammonium or a N-oxide, (3) a group which is        bonded via the sulfur atom, (4) a group represented by formula:        wherein ek is 0 or 1, the phosphorus atom may form a phosphonium        salt when ek is 0, and each of R^(e5′) and R^(e6′) is a        hydrocarbon atom which may be substituted, a hydroxyl group        which may be substituted, or an amino group which may be        substituted, and R^(e5′) and R^(e6′) may bond to each other to        form a cyclic ring group together with the adjacent phosphorus        atom, (5) an amidino group which may be substituted or (6) a        guanidino group which may be substituted, or a salt thereof;    -   (2) An agent for the prevention or treatment of chronic        rheumatoid arthritis, autoimmune diseases, allergic disorders,        ischemic brain cell damage, myocardial infarction, chronic        nephritis, and arteriosclerosis which comprises a compound        having a CCR antagonistic effect represented by the formula:        wherein R^(a1) is a hydrogen atom, a hydrocarbon group which may        be substituted, a non-aromatic heterocyclic group which may be        substituted, R^(a2) is a hydrocarbon group which may be        substituted, a non-aromatic heterocyclic group which may be        substituted, or R^(a1) and R^(a2) may combine with each other        together with A^(a) to form a heterocyclic group which may be        substituted, A^(a) is N or N⁺—R^(a5).Y^(a−) (R^(a5) is a        hydrocarbon group, Y^(a−) is a counter anion), R^(a3) is a        cyclic hydrocarbon group which may be substituted or a        heterocyclic group which may be substituted, na is 0 or 1,        R^(a4) is a hydrogen atom, a hydrocarbon group which may be        substituted, a heterocyclic group which may be substituted, an        alkoxy group which may be substituted, an aryloxy group which        may be substituted, or an amino group which may be substituted,        E^(a) is a divalent aliphatic hydrocarbon group which may be        substituted by a group other than an oxo group, G^(a1) is a        bond, CO or SO₂, G^(a2) is CO, SO₂, NHCO, CONH or OCO, J^(a) is        methine or a nitrogen atom, and each of Q^(a) and R^(a) is a        bond or a divalent C₁₋₃ aliphatic hydrocarbon which may be        substituted, with the proviso that J^(a) is methine when G^(a2)        is OCO, one of Q^(a) and R^(a) is not a bond when the other is a        bond, and each of Q^(a) and R^(a) is not substituted by an oxo        group when G^(a1) is a bond,        the formula:        wherein R^(b1) is a hydrocarbon group which may be substituted;        R^(b2) is a cyclic hydrocarbon group which may be substituted or        a heterocyclic group which may be substituted; R^(b3) is a        halogen atom, a carbamoyl group which may be substituted, a        sulfamoyl group which may be substituted, an acyl group derived        from a sulfonic acid, a C₁₋₄ alkyl group which may be        substituted, a C₁₋₄ alkoxy group which may be substituted, an        amino group which may be substituted, a nitro group or a cyano        group; R^(b4) is a hydrogen atom or a hydroxy group; nb is an        integer of 0 or 1; pb is an integer of 0 or 1 to 4,        the formula:        wherein R^(c1) is a hydrocarbon group, R^(c2) is a hydrocarbon        group having 2 or more carbon atoms, or R^(c1) and R^(c2) may be        bound together with the adjacent nitrogen atom to form a ring        which may have a substituent or substituents, R^(c3) is a        hydrocarbon group which may have a substituent or substituents        or a heterocyclic group which may have a substituent or        substituents, R^(c4) is a hydrogen atom, a hydrocarbon group        which may have a substituent or substituents or a heterocyclic        group which may have a substituent or substituents, E^(c) is a        divalent aliphatic hydrocarbon group which may have a        substituent or substituents other than an oxo group, G^(c) is CO        or SO₂, J^(c) is a nitrogen atom or a methine group which may        have a substituent or substituents, and Q^(c) and R^(c) are each        a bond or a divalent aliphatic C₁₋₃ hydrocarbon group which may        have a substituent or substituents,        the formula:        wherein A^(d) is a group represented by the formula:        wherein, R^(d3) is (1) a hydrocarbon group which may be        substituted, (2) a C₁₋₄ alkoxy group which may be substituted        or (3) an amino group which may be substituted; X^(d) is a bond,        —SO₂— or —CO—; nd is an integer of 1 to 3; md is 0 or an integer        of 1 to 3; R^(d4) and R^(d5) are the same or different and each        of which is a hydrogen atom or a C₁₋₆ alkyl group; R^(d6) is a        hydroxyl group, a C₁₋₆ alkyl group or a C₂₋₆ alkenyl group; rd        is an integer of 2 to 4; B^(d) is a bond, —CH₂—, —SO₂—, —SO—,        —S—, —O—, —CO—, —NR^(da)—SO₂— or —NR^(da)—CO— (wherein, R^(da)        is a hydrogen atom, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group or        a C₃₋₈ cycloalkyl group); each of pd and qd is 0 or an integer        of 1 to 4; R^(d1) is a halogen atom, a C₁₋₆ alkyl group, a C₂₋₄        alkenyl group, a C₁₋₄ alkanoyl group, a C₁₋₄ alkoxy group, a        cyano group, a trifloromethyl group, a nitro group, a hydroxyl        group, an amino group or an amidino group; R^(d2) is 1) a        halogen, 2) a C₁₋₆ alkyl which may be substituted by a halogen        or a C₁₋₄ alkoxy, 3) a C₁₋₄ alkoxy which may be substituted by a        halogen or a C₁₋₄ alkoxy, 4) nitro, 5) cyano, 6) hydroxyl, 7) a        C₁₋₄ alkanoylamino, 8) SO₂NR^(db)R^(dc), 9) SO₂R^(dd), 10)        CONR^(db)R^(dc), 11) NR^(db)R^(dc) or 12) NR^(da)—SO₂R^(dd)        (wherein, R^(da) has the meaning given above, and R^(db) and        R^(dc) may be the same or different, and are (1) a hydrogen        atom, (2) a C₁₋₆ alkyl group which may be substituted by a        halogen or a C₁₋₄ alkoxy, or (3) a C₃₋₈ cycloalkyl group which        may be substituted by a halogen or a C₁₋₄ alkoxy, or R^(db) and        R^(dc) may bond with a nitrogen atom to form a cyclic amino        group and R^(dd) is a C₁₋₆ alkyl group or a C₃₋₈ cycloalkyl        group), each R^(d1) may be the same or different from each other        when pd is two or more, and each R^(d2), may be the same or        different from each other when qd is two or more, or        the formula:        R^(e1)—X^(e1)—W^(e)—X^(e2)-Z^(e1)-Z^(e2)—R^(e2)  (eI)        wherein R^(e1) represents a 5 to 6-membered cyclic ring group        which may be substituted, X^(e1) represents a bond or a bivalent        group, in which the number of atoms constituting the        straight-chain portion is 1 to 4, W^(e) represents a bivalent        group represented by formula:        wherein each of ring A^(e) and ring B^(e) represents a 5- to        7-membered cyclic group which may be substituted, each of Ee₁        and Ee₄ is a carbon atom which may be substituted or a nitrogen        atom which may be substituted, each of Ee₂ and Ee₃ is a carbon        atom which may be substituted, a nitrogen atom which may be        substituted, or a sulfur atom which may be oxidized or an oxygen        atom, each of a^(e) and b^(e) is a single bond or a double        bond), X^(e2) is a bivalent group in which the number of atoms        constituting the straight-chain portion is 1 to 4, Z^(e1) is a        bond or a bivalent cyclic ring group, Z^(e2) is a bond or a        bivalent cyclic ring group in which the number of atoms        constituting the straight-chain portion is 1 to 4, and R^(e2)        is (1) an amino group which may be substituted, and the nitrogen        atom may be converted into a quaternary ammonium or an        N-oxide, (2) a nitrogen-containing heterocyclic ring group which        may be substituted, may contain sulfur atom or an oxygen atom as        a ring-constituting atom, and the nitrogen atom may be converted        into a quaternary ammonium or a N-oxide, (3) a group which is        bonded via the sulfur atom, (4) a group represented by formula:        wherein ek is 0 or 1, the phosphorus atom may form a phosphonium        salt when ek is 0, and each of R^(e5′) and R^(e6′) is a        hydrocarbon atom which may be substituted, a hydroxyl group        which may be substituted, or an amino group which may be        substituted, and R^(e5′) and R^(e6′) may bond to each other to        form a cyclic ring group together with the adjacent phosphorus        atom), (5) an amidino group which may be substituted or (6) a        guanidino group which may be substituted, or a salt thereof;    -   (3) The agent for the prevention or treatment according to the        above (1) or (2), wherein the compound having a CCR antagonistic        effect or a salt thereof is        N-(3,4-dichlorophenyl)-1-(methylsulfonyl)-N-{3-[4-({4-[(methylsulfonyl)-amino]phenyl}sulfonyl)-1-piperidinyl]propyl}-4-piperidinecarboxamide,        N-(3-chlorophenyl)-1-(methylsulfonyl)-N-(3-{4-[4-(methylsulfonyl)benzyl]-1-piperidinyl}propyl)-4-piperidinecarboxamide,        N-(3-{4-[4-(aminocarbonyl)benzyl]-1-piperidinyl}propyl)-N-(3,4-dichlorophenyl)-1-(methylsulfonyl)-4-piperidinecarboxamide,        1-acetyl-N-(3-{4-[4-(aminocarbonyl)benzyl]-1-piperidinyl}propyl)-N-(3-chloro-4-methylphenyl)-4-piperidinecarboxamide,        N-(3,4-dichlorophenyl)-N-(3-{4-[4-(ethylsulfonyl)benzyl]-1-piperidinyl}propyl)-1-(methylsulfonyl)-4-piperidinecarboxamide,        N-(3,4-dichlorophenyl)-N-(3-{4-[4-(isopropylsulfonyl)benzyl]-1-piperidinyl}propyl)-1-(methylsulfonyl)-4-piperidinecarboxamide,        N-(3-chlorophenyl)-N-(3-{4-[4-(isopropylsulfonyl)benzyl]-1-piperidinyl}propyl)-1-(methylsulfonyl)-4-piperidinecarboxamide,        N-(3-chlorophenyl)-N-(3-{4-[4-(ethylsulfonyl)benzyl]-1-piperidinyl}propyl)-1-(methylsulfonyl)-4-piperidinecarboxamide,        N-(3,4-dichlorophenyl)-1-(methylsulfonyl)-N-(3-{4-[4-(methylsulfonyl)benzyl]-1-piperidinyl}propyl)-4-piperidinecarboxamide,        N-(3-{4-[4-(aminocarbonyl)benzyl]-1-piperidinyl}propyl)-N-(3-chloro-4-methylphenyl)-1-(methylsulfonyl)-4-piperidinecarboxamide,        N-[3-(4-benzyl-1-piperidinyl)propyl]-N′-(4-chlorophenyl)-N-phenylurea,        N′-(4-chlorophenyl)-N-{3-[4-(4-fluorobenzyl)-1-piperidinyl]propyl}-N-phenylurea,        N′-(4-chlorophenyl)-N-(3-{4-[4-(4-morpholinylsulfonyl)benzyl]-1-piperidinyl}propyl)-N-phenylurea,        N′-(4-chlorophenyl)-N-(3-{4-[4-(4-methylsulfonyl)benzyl]-1-piperidinyl}propyl)-N-phenylurea,        4-{[1-(3-{[(4-chloroanilino)carbonyl]anilino}propyl)-4-piperidinyl]methyl}benzamide,        N-[3-(4-benzyl-1-piperidinyl)propyl]-N-(3,4-dichlorophenyl)-1-methyl-5-oxo-3-pyrrolidinecarboxamide,        1-benzyl-N-[3-(4-benzyl-1-piperidinyl)propyl]-5-oxo-N-phenyl-3-pyrrolidinecarboxamide,        N-[3-(4-benzyl-1-piperidinyl)propyl]-1-(2-chlorobenzyl)-5-oxo-N-phenyl-3-pyrrolidinecarboxamide,        N-(3,4-dichlorophenyl)-N-{3-[4-(4-fluorobenzyl)-1-piperidinyl]propyl}-1-methyl-5-oxo-3-pyrrolidinecarboxamide,        N-[3-(4-benzyl-1-piperidinyl)propyl]-5-oxo-N-phenyl-1-(2,2,2-trifluoroethyl)-3-pyrrolidinecarboxamide,        N-(3,4-dichlorophenyl)-N-(3-{4-[4-(methylsulfonyl)benzyl]-1-piperidinyl}propyl)-2-[1-(methylsulfonyl)-4-piperidinyl]acetamide,        N-(3,4-dichlorophenyl)-N-(3-{4-[4-(isopropylsulfonyl)benzyl]-1-piperidinyl}propyl)-2-[1-(methylsulfonyl)-4-piperidinyl]acetamide,        3-(1-acetyl-4-piperidinyl)-N-(3,4-dichlorophenyl)-N-(3-{4-[4-(methylsulfonyl)benzyl]-1-piperidinyl}propyl)propanamide,        or        N-(3,4-dichlorophenyl)-4-hydroxy-1-(methylsulfonyl)-N-(3-{4-[4-(methylsulfonyl)benzyl]-1-piperidinyl}propyl)-4-piperidinecarboxamide        or a salt thereof;    -   (4) The prevention or treatment agent according to the above (1)        or (2), wherein the compound having a CCR antagonistic effect or        a salt thereof is.        N-methyl-N-[4-[[[2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]carbonyl]amino]benzyl]piperidinium        iodide,        N-methyl-N-[4-[[[7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4-yl]carbonyl]amino]benzyl]piperidinium        iodide,        N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4-carboxamide,        N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-(4-morpholinophenyl)-2,3-dihydro-1-benzoxepin-4-carboxamide,        7-(4-ethoxyphenyl)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-2,3-dihydro-1-benzoxepin-4-carboxamide,        N,N-dimethyl-N-[4-[[[2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]carbonyl]amino]benzyl]-N-(tetrahydropyran-4-yl)ammonium        iodide,        N-methyl-N-[4-[[[7-(4-methylphenyl)-3,4-dihydronaphthalen-2-yl]carbonyl]amino]benzyl]piperidinium        iodide,        N,N-dimethyl-N-(4-(((2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl)carbonyl)amino)benzyl)-N-(4-tetrahydropyranyl)ammonium        chloride,        N,N-dimethyl-N-(((7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4-yl)carbonyl)amino)benzyl)-N-(4-oxocyclohexyl)ammonium        chloride,        N-(4-(((7-(4-ethoxyphenyl)-2,3-dihydro-1-benzoxepin-4-yl)carbonyl)amino)benzyl)-N,N-dimethyl-N-(4-tetrahydropyranyl)ammonium        chloride,        N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-(4-propoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide,        7-(4-butoxyphenyl)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide,        7-[4-[N-methyl-N-(2-propoxyethyl)amino]phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide,        7-[4-(2-ethoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide,        N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-[4-(2-propoxyethoxy)phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide,        7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide,        7-[4-(2-ethoxyethoxy)-3,5-dimethylphenyl]-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide,        7-[2-chloro-4-(2-propoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide,        7-(3-methyl-4-propoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide,        7-(3,4-dipropoxyphenyl)-N-(4-((N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino)methyl)phenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide,        7-[4-(2-ethoxyethoxy)phenyl]-1-ethyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,        1-ethyl-7-[4-(2-propoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,        7-[4-(2-butoxyethoxy)phenyl]-1-ethyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,        7-[4-(2-ethoxyethoxy)phenyl]-1-formyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,        1-formyl-7-[4-(2-propoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,        7-[4-(2-butoxyethoxy)phenyl]-1-formyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,        7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-5-yl)amino]methyl]phenyl]-1-propyl-2,3-dihydro-1-benzoazepin-4-carboxamide,        N-[4-[[N-methyl-N-(tetrahydropyran-5-yl)amino]methyl]phenyl]-7-[4-(2-propoxyethoxy)phenyl]-1-propyl-2,3-dihydro-1-benzoazepin-4-carboxamide,        1-benzyl-7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,        7-[4-(2-butoxyethoxy)phenyl]-1-cyclopropylmethyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,        7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-phenyl-2,3-dihydro-1-benzoazepin-4-carboxamide,        7-[4-(2-butoxyethoxy)phenyl]-1-(3,4-methylenedioxy)phenyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,        7-[4-(2-butoxyethoxy)phenyl]-1-(2-methyloxazol-5-yl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,        1-allyl-7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,        7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(3-thienyl)methyl-2,3-dihydro-1-benzoazepin-4-carboxamide,        7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(thiazol-2-yl)methyl-2,3-dihydro-1-benzoazepin-4-carboxamide,        7-[4-(2-butoxyethoxy)phenyl]-1-(1-methylpyrazol-4-yl)methyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,        7-[4-(2-butoxyethoxy)phenyl]-1-(3-methylisothiazol-5-yl)methyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,        7-[4-(2-butoxyethoxy)phenyl]-1-(1-ethylpyrazol-4-yl)methyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,        7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[N-methyl-N-(tetrahydropyran-5-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,        1-isobutyl-N-[4-[[N-methyl-N-(tetrahydropyran-5-yl)amino]methyl]phenyl]-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,        7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(thiazol-5-yl)methyl-2,3-dihydro-1-benzoazepin-4-carboxamide,        7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(1-methyltetrazol-5-yl)methyl-2,3-dihydro-1-benzoazepin-4-carboxamide,        or        7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(2-methyltetrazol-5-yl)methyl-2,3-dihydro-1-benzoazepin-4-carboxamide        or a salt thereof;    -   (5) A method of preventing or treating graft-versus host disease        and/or rejection reactions during organ or bone marrow        transplantation, which comprises the step of administering an        effective amount of a compound having a CCR antagonist effect to        a mammal;    -   (6) A method of preventing or treating chronic rheumatoid        arthritis, autoimmune diseases, allergic disorders, ischemic        brain cell damage, myocardial infarction, chronic nephritis, and        arteriosclerosis, which comprises the step of administering an        effective amount of a compound having a CCR antagonist effect to        a mammal;    -   (7) Use of a compound having a CCR antagonist effect for        manufacturing an agent for the prevention or treatment of        graft-versus host disease and/or rejection reactions during        organ or bone marrow transplantation;    -   (8) Use of a compound having a CCR antagonist effect for        manufacturing an agent for the prevention or treatment of        chronic rheumatoid arthritis, autoimmune diseases, allergic        disorders, ischemic brain cell damage, myocardial infarction,        chronic nephritis, and arteriosclerosis; and the like.

DETAILED DESCRIPTION OF THE INVENTION

The following compounds are examples of the compound represented by theabove formula (eI) or salt thereof.

-   -   1) the prevention and treatment agent disclosed in (1) above        that is a compound represented by the formula:        wherein R^(e1) is an optionally substituted 5- to 6-membered        ring, W^(ea) is a divalent group represented by the formula:        wherein the ring A^(ea) is an optionally substituted 5- to        6-membered aromatic ring, X^(ea) is an optionally substituted        carbon atom, an optionally substituted nitrogen atom, a sulfur        atom or an oxygen atom, the ring B^(e) is an optionally        substituted 5- to 7-membered ring; Z^(e2) is a bond or a        divalent group in which the number of carbon atoms constituting        the straight-chain portion is 1 to 4, R^(e2a) is (1) an        optionally substituted amino group in which a nitrogen atom may        form a quaternary ammonium, (2) an optionally substituted        nitrogen-containing heterocyclic ring group which may contain a        sulfur atom or an oxygen atom as ring constituting atoms and        wherein a nitrogen atom may form a quaternary ammonium, (3) a        group binding through a sulfur atom or (4) a group of the        formula:        wherein ek is 0 or 1, and when ek is 0, a phosphorus atom may        form a phosphonium; and R^(e5) and R^(e6) are independently an        optionally substituted hydrocarbon group or an optionally        substituted amino group, and R^(e5) and R^(e6) may bind to each        other to form a cyclic group together with the adjacent        phosphorus atom, or salt thereof,    -   2) the prevention and treatment agent disclosed in (1) above        that is a compound represented by the formula:        wherein R^(e1b) is an optionally substituted phenyl group or an        optionally substituted thienyl group; Y^(eb) is —CH₂—, —O— or        —S—; and R^(e2b), R^(e3b) and R^(e4b) are independently an        optionally substituted aliphatic hydrocarbon group or an        optionally substituted alicyclic heterocyclic ring group, or        salt thereof,    -   3) the prevention and treatment agent disclosed in (1) above        that is a compound represented by the formula:        wherein R^(e1) is an optionally substituted 5- to 6-membered        ring; the ring A^(ec) is an optionally substituted 6- to        7-membered ring; the ring B^(ec) is an optionally substituted        benzene ring; n^(ec) is an integer of 1 or 2; Z^(e2) is a bond        or a divalent group in which the number of carbon atoms        constituting the straight-chain is 1 to 4; R^(e2c) is (1) an        optionally substituted amino group in which a nitrogen atom may        form a quaternary ammonium, (2) an optionally substituted        nitrogen-containing heterocyclic ring group which may contain a        sulfur atom or an oxygen atom as ring constituting atoms and        wherein a nitrogen atom may form a quaternary ammonium, (3) a        group binding through a sulfur atom or (4) a group of the        formula:        wherein ek is 0 or 1, and when ek is 0, a phosphorus atom may        form a phosphonium; and R^(e5′) and R^(e6′) are independently an        optionally substituted hydrocarbon group, an optionally        substituted hydroxy group or an optionally substituted amino        group, and R^(e5′) and R^(e6′) may bind to each other to form a        cyclic group together with the adjacent phosphorus atom, or a        salt thereof,    -   4) a compound represented by the formula:        wherein R^(e1d) is a 5- to 6-membered aromatic ring which has a        group of the formula: R^(ed)-Z^(e1d)—X^(ed)-Z^(e2d)— wherein        R^(ed) is a hydrogen atom or an optionally substituted        hydrocarbon group, X^(ed) is an optionally substituted alkylene        chain, and Z^(e1d) and Z^(e2d) are respectively hetero-atoms,        and which may have a further substituent, the group R^(ed) may        bind to the 5-6 membered aromatic ring to form a ring, Y^(ed) is        an optionally substituted imino group, R^(e2d) and R^(e3d) are        respectively an optionally substituted aliphatic hydrocarbon        group or an optionally substituted alicyclic heterocyclic group,        or a salt thereof.

In the formula (I), the “hydroxarbon group” in the “hydrocarbon groupwhich may be substituted” represented by R^(a1) includes e.g. analiphatic chain hydrocarbon group, an alicyclic hydrocarbon group and anaryl group, preferably, an aliphatic chain hydrocarbon group and analicyclic hydrocarbon group.

Examples of the aliphatic hydrocarbon group include e.g. astraight-chain or branched aliphatic hydrocarbon group such as an alkylgroup, an alkenyl group, an alkynyl group, etc., preferably an alkylgroup. Examples of the alkyl group include e.g. a C₁₋₁₀ alkyl group(preferably a C₁₋₆ alkyl, etc.) such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl,1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl,3,3-dimethylpropyl, 2-ethylbutyl, n-heptyl, 1-methylheptyl,1-ethylhexyl, n-octyl, 1-methyl-heptyl, nonyl, etc. Examples of thealkenyl group include e.g. a C₂₋₆ alkenyl group such as vinyl, allyl,isopropenyl, 2-methyl-allyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl,2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl,3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,5-hexenyl, etc. Examples of the alkynyl group include e.g. a C₂₋₆alkynyl group such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl,2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl,1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc.

Examples of the alicyclic hydrocarbon group include e.g. a saturated orunsaturated alicyclic hydrocarbon group such as a cycloalkyl group, acycloalkenyl group, a cycloalkanedienyl group, etc., preferablycycloalkyl group. Examples of the cycloalkyl group include e.g. a C₃₋₉cycloalkyl (preferably a C₃₋₈ cycloalkyl) such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclononyl, etc., and a fused ring such as 1-indanyl, 2-indanyl, etc.Examples of the cycloalkenyl group include e.g. a C₃₋₆ cycloalkenylgroup such as 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl,3-cyclohexen-1-yl, 1-cyclobuten-1-yl, 1-cyclopenten-1-yl, etc. Examplesof the cycloalkanedienyl group include e.g. a C₄₋₆ cycloalkanedienylgroup such as 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl,2,5-cyclohexadien-1-yl, etc.

Examples of the aryl group include e.g. a monocyclic or fused polycyclicaromatic hydrocarbon group. Among others, a C₆₋₁₄ aryl group such asphenyl, naphthyl, anthryl, phenathryl, acenaphthylenyl, 4-indanyl,5-indanyl, etc. are preferable. In particular, phenyl, 1-naphthyl,2-naphthyl, etc. are preferable.

Examples of the “non-aromatic heterocyclic group” in the “optionallysubstituted non-aromatic heterocyclic group” represented by R^(a1)include a 3- to 8-membered (preferably 5- or 6-membered) saturated orunsaturated (preferably saturated) non-aromatic heterocyclic group(alicyclic heterocyclic group) such as oxiranyl, azetidinyl, oxetanyl,thiethanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidinyl,tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, etc.

Examples of the substituent of the “optionally substituted hydrocarbongroup” and “optionally substituted non-aromatic heterocyclic group”represented by R^(a1) include an optionally substituted alkyl group, anoptionally substituted alkenyl group, an optionally substituted alkynylgroup, an optionally substituted aryl group, an optionally substitutedcycloalkyl or cycloalkenyl group, an optionally substituted heterocyclicgroup, an optionally substituted amino group, an optionally substitutedimidoyl group, an optionally substituted amidino group, an optionallysubstituted hydroxyl group, an optionally substituted thiol group, anoptionally esterified carboxyl group, an optionally substitutedcarbamoyl group, an optionally substituted thiocarbamoyl group, anoptionally substituted sulfamoyl group, a halogen atom (e.g. fluorine,chlorine, bromine, iodine, etc., preferably chlorine, bromine, etc.), acyano group, a nitro group, an acyl group derived from a sulfonic acid,an acyl group derived from an carboxylic acid, an optionally substitutedalkyl-sulfinyl group, an optionally substituted aryl-sulfinyl group,etc. The optionally substituted hydrocarbon group and optionallysubstituted non-aromatic heterocyclic group may have 1 to 5 substituentsas described above (preferably 1 to 3 substituents) at any possibleposition.

Examples of the aryl group in the “optionally substituted aryl group” asthe substituent include a C₆₋₁₄ aryl group such as phenyl, naphthyl,anthryl, phenathryl, acenaphthylenyl, etc. Examples of the substituentof the aryl group include a lower alkoxy group which may be substitutedby halogen (e.g. a C₁₋₆ alkoxy group such as methoxy, ethoxy, propoxy,etc., a C₁₋₄ alkoxy group substituted by halogen such as fluoromethoxy,difluoromethoxy, trifluoromethoxy, 1,1-difluoroethoxy,2,2-difluoroethoxy, 3,3-difluoropropoxy, 2,2,3,3,3-pentafluoropropoxy,etc.), an aryloxy which may be substituted (e.g., phenoxy,4-fluorophenoxy, 2-carbamoylphenoxy, etc.), a halogen atom (e.g.,fluorine, chlorine, bromine, iodine, etc.), a lower alkyl group whichmay be substituted (an unsubstituted C₁₋₆ alkyl group such as methyl,ethyl, propyl, etc., a C₁₋₄ alkyl group substituted by halogen such asfluoromethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl,2,2-difluoroethyl, 3,3-difluoropropyl, 2,2,3,3,3-pentafluoropropyl,etc.), a C₃₋₈ cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, etc.), an amino group, a mono-substituted amino(e.g., carbamoylamino, methylsulfonylamino, methylamino, ethylamino,propylamino, etc.), di-substituted amino (e.g., dimethylamino,diethylamino, N-methyl-N-methylsulfonylamino, di(methylsulfonyl)amino,etc.), a carbamoyl group which may be substituted by a C₁₋₆ alkyl (e.g.,butylcarbamoyl, etc.), formyl, a C₂₋₆ alkanoyl group (e.g., a C₂₋₆alkanoyl such as acetyl, propionyl, butyryl, etc.), a C₆₋₁₄ aryl group(e.g., phenyl, naphthyl, etc.), a C₆₋₁₄ aryl carbonyl (e.g., benzoyl,naphthoyl, etc.), a C₇₋₁₃ aralkyl carbonyl (e.g., benzylcarbonyl,naphthylmethylcarbonyl, etc.), a hydroxyl group, an alkanoyloxy (a C₂₋₅alkanoyloxy such as acetyloxy, propionyloxy, butyryloxy, etc.), a C₇₋₁₃aralkyl-carbonyloxy (e.g., benzylcarbonyloxy, etc.), a nitro group, asulfamoyl group which may be substituted (e.g., unsubstituted sulfamoylgroup, N-methylsulfamoyl, etc.), an arylthio group which may besubstituted (e.g., phenylthio, 4-methylphenylthio, etc.), —N═N-phenyl, acyano group, an amidino group, a carboxyl group which may be esterified(free carboxyl group, and a C₁₋₄ alkoxy carbonyl such asmethoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc., etc.), a C₁₋₆alkylthio, a C₁₋₆ alkylsulfinyl, a C₁₋₆ alkylsulfonyl, a C₆₋₁₄ arylthio,a C₆₋₁₄ arylsulfinyl, a C₆₋₁₄ arylsulfonyl, a heterocyclic group whichmay be substituted (e.g., pyridyl, thienyl, tetrazolyl, morpholinyl,oxazolyl, etc. and those as mentioned below for the definition ofheterocyclic group which may be substituted shown as R^(a3)), etc. Oneor two of these substituents, may be present at any substitutableposition.

Examples of the cycloalkyl group in the “optionally substitutedcycloalkyl group” as the substituent include e.g. a C₃₋₇ cycloalkylgroup such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, etc. Examples of the substitutent of the cycloalkyl groupsmay have the same number and kind of substituents as those of the abovedescribed “optionally substituted aryl group”.

Examples of the cycloalkenyl group in the “optionally substitutedcycloalkenyl group” as the substituent include e.g. a C₃₋₆ cycloalkenylgroup such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,etc. Example of the substitutent of the cycloalkenyl groups which may besubstituted may have the same number and kind of substituents as thoseof the above described “optionally substituted aryl group”.

Examples of the alkyl group in the “optionally substituted alkyl group”as the substituent include e.g. a C₁₋₆ alkyl etc. such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl,1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl,3,3-dimethylpropyl, etc. Examples of the susbstitutent of the alkylgroups may have the same number and kind of substituents as those of theabove described “optionally substituted aryl group”.

Examples of the alkenyl group in the “optionally substituted alkenylgroup” as the substituent include e.g. a C₂₋₆ alkenyl group such asvinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl,2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 4-hexenyl, 5-hexenyl, etc. Examples of the substitutents ofthe alkenyl groups may have the same number and kind of substituents asthose of the above described “optionally substituted aryl group”.

Examples of the alkynyl group in the “optionally substituted alkynylgroup” as the substituent include e.g. a C₂₋₆ alkynyl group such asethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl,3-hexynyl, 4-hexynyl, 5-hexynyl, etc. Examples of the substituent of thealkynyl groups may have the same kind and number of substituents asthose of the above described “optionally substituted aryl group”.

Examples of the heterocyclic group in the “optionally substitutedheterocyclic group” as the substituent include e.g. an aromaticheterocyclic group, saturated or unsaturated non-aromatic heterocyclicgroup (alicyclic heterocyclic group) etc., which contains at least onehetero-atom (preferably 1 to 4 hetero-atoms, more preferably 1 to 2hetero-atoms) consisting of 1 to 3 kinds of hetero-atoms (preferably 1to 2 kinds of hetero-atoms) selected from an oxygen atom, a sulfur atom,a nitrogen atom, etc.

Examples of the “aromatic heterocyclic group” include an aromaticmonocyclic heterocyclic group such as a 5- to 6-membered aromaticmonocyclic heterocyclic group (e.g. furyl, thienyl, pyrrolyl, oxazolyl,isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, etc.); an aromatic fused heterocyclicgroup such as a 8- to 12-membered aromatic fused heterocyclic group(e.g. benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl,1H-indazolyl, benzindazolyl, benzoxazolyl, 1,2-benzoisooxazolyl,benzothiazolyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl,isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl,naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl,β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl,phenazinyl, phenoxathinyl, thianthrenyl, phenanthridinyl,phenanthrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl,pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl,imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl,1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl, etc.);etc., preferably, a heterocyclic group consisting of the above-mentioned5- or 6-membered aromatic monocyclic heterocyclic group fused with abenzene ring or a heterocyclic group consisting of the above-mentioned5- or 6-membered aromatic monocyclic heterocyclic group fused with thesame or different above-mentioned 5- or 6-membered aromatic monocyclicheterocyclic group, etc.

Examples of the “non-aromatic heterocyclic group” include e.g. a 3- to8-membered (preferably 5- or 6-membered) saturated or unsaturated(preferably saturated) non-aromatic heterocyclic group (alicyclicheterocyclic group) such as oxiranyl, azetidinyl, oxetanyl, thiethanyl,pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidinyl,tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, etc.

Examples of the substituent of the “optionally substituted heterocyclicgroup” as the substituent include a lower alkyl group (e.g. a C₁₋₆ alkylgroup such as methyl, ethyl, propyl, etc.), an acyl group (e.g. a C₁₋₆alkanoyl such as formyl, acetyl, propionyl, pivaloyl, etc., e.g. an arylcarbonyl such as benzoyl, etc., e.g. a C₁₋₆ alkylsulfonyl such asmethylsulfonyl, ethylsulfonyl, etc., e.g. a substituted sulfonyl such asaminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl, etc.), alower alkyl substituted by a halogen (e.g., trifluoromethyl,1,1-difluoroethyl, etc.), etc.

Examples of the substituent in the “optionally substituted amino group”,“optionally substituted imidoyl group”, “optionally substituted amidinogroup”, “optionally substituted hydroxyl group” and “optionallysubstituted thiol group” as the substituent include e.g. a lower alkylgroup (e.g. a C₁₋₆ alkyl group such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, t-butyl, pentyl, hexyl, etc.), aryl group (e.g.,phenyl, 4-methylphenyl, etc.), acyl group (C₁₋₆ alkanoyl (e.g., formyl,acetyl, propionyl, pivaloyl, etc.), e.g. aryl-carbonyl (e.g. benzoyl,etc.), C₁₋₆ alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, etc.),C₆₋₁₄ aryl-sulfonyl (e.g., para-toluenesulfonyl, etc.), etc.,substituted-sulfonyl such as aminosulfonyl, methylaminosulfonyl,dimethylaminosulfonyl, etc.), an optionally halogenated C₁₋₆alkoxy-carbonyl (e.g. trifluoromethoxycarbonyl,2,2,2-trifluoroethoxycarbonyl, trichloromethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, etc.), etc. In addition, the “aminogroup” in the “optionally substituted amino group” as the substituentmay be substituted with an optionally substituted imidoyl group (e.g., aC₁₋₆ alkylimidoyl, formimidoyl, amidino, etc.), etc. and twosubstituents of the “amino group” may form a cyclic amino group togetherwith a nitrogen atom. Examples of the cyclic amino group include e.g. 3-to 8-membered (preferably 5- to 6-membered) cyclic amino group such as1-azetidinyl, 1-pyrrolidinyl, piperidinol-piperidinyl,morpholino4-morpholinyl, 1-piperazinyl and 1-piperazinyl which may haveat the 4-position a lower alkyl group (e.g. a C₁₋₆ alkyl group such asmethyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, etc.),an aralkyl group (e.g. a C₇₋₁₀ aralkyl group such as benzyl, phenethyl,etc.), an aryl group (e.g. a C₆₋₁₀ aryl group such as phenyl,1-naphthyl, 2-naphthyl, etc.), etc.

Examples of the “optionally substituted carbamoyl group” includeunsubstituted carbamoyl, as well as a N-mono-substituted carbamoyl groupand a N,N-di-substituted carbamoyl group.

The “N-mono-substituted carbamoyl group” is a carbamoyl group having onesubstituent on the nitrogen atom and the substituent include e.g. alower alkyl group (e.g. a C₁₋₆ alkyl group such as methyl, ethyl,propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, etc.), acycloalkyl group (e.g. a C₃₋₆ cycloalkyl group such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, etc.), an aryl group (e.g. a C₆₋₁₀aryl group such as phenyl, 1-naphthyl, 2-naphthyl, etc.), an aralkylgroup (e.g. a C₇₋₁₀ aralkyl group such as benzyl, phenethyl, etc.,preferably a phenyl-C₁₋₄ alkyl group etc.), a heterocyclic group (e.g.the same substituent as those in the above described “heterocyclicgroup” as the substituent of the “optionally substituted hydrocarbongroup” represented by R^(a1), etc.), etc. The the lower alkyl group, thecycloalkyl group, the aryl group, the aralkyl group and the heterocyclicgroup may have a substituent and examples of the substituent includee.g. a hydroxyl group, an optionally substituted amino group [the aminogroup may have 1 to 2 substituents (e.g. a lower alkyl group (e.g. aC₁₋₆ alkyl group such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, t-butyl, pentyl, hexyl, etc.), an acyl group (e.g. a C₁₋₆alkanoyl such as formyl, acetyl, propionyl, pivaloyl, etc., anaryl-carbonyl such as benzoyl, etc., a C₁₋₆ alkylsulfonyl such asmethylsulfonyl, ethylsulfonyl, etc.), etc.)], a halogen atom (e.g.fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyanogroup, a lower alkyl group optionally substituted with 1 to 5 halogenatoms (e.g. fluorine, chlorine, bromine, iodine, etc.), a lower alkoxygroup optionally substituted with 1 to 5 halogen atoms (e.g. fluorine,chlorine, bromine, iodine, etc.), etc. The lower alkyl group includese.g. a C₁₋₆ alkyl group such as methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. and inparticular methyl, ethyl, etc. are preferable. The lower alkoxy groupincludes e.g. a C₁₋₆ alkoxy group such as methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc. and inparticular methoxy, ethoxy, etc. are preferable. It is preferable thatone, two or three substituents, more preferably two substituents arepresent.

The “N,N-di-substituted carbamoyl group” is a carbamoyl group having twosubstituents on the nitrogen atom. Examples of one of the substituentsinclude the same as those of the above described “N-mono-substitutedcarbamoyl group” and examples of the other substituent include e.g. alower alkyl group (e.g. a C₁₋₆ alkyl group such as methyl, ethyl,propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, etc.), a C₃₋₆cycloalkyl group (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,etc.), a C₇₋₁₀ aralkyl group (e.g. benzyl, phenethyl, etc., preferablyphenyl-C₁₋₄ alkyl group, etc.), etc. In addition, two substituents ofthe “N,N-di-substituted carbamoyl group” may form a cyclic amino grouptogether with a nitrogen atom. Examples of the cyclic amino-carbamoylgroup include e.g. 3- to 8-membered (preferably 5- to 6-membered) cyclicamino-carbamoyl group such as 1-azetidinylcarbonyl,1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, 4-morpholinylcarbonyl,1-piperazinylcarbonyl and 1-piperazinylcarbonyl which may have at the4-position a lower alkyl group (e.g. a C₁₋₆ alkyl group such as methyl,ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, etc.), anaralkyl group (e.g. a C₇₋₁₀ aralkyl group such as benzyl, phenethyl,etc.), an aryl group (e.g. a C₆₋₁₀ aryl group such as phenyl,1-naphthyl, 2-naphthyl, etc.), etc.

Examples of the substituent in the “optionally substituted thiocarbamoylgroup” include the same substituent as those in the above described“optionally substituted carbamoyl group”.

Examples of the “sulfamoyl group which may be substituted” include anunsubstituted-sulfamoyl group, a N-mono-substituted sulfamoyl group anda N,N-di-substituted sulfamoyl group.

The “N-mono-substituted sulfamoyl group” is a sulfamoyl group having onesubstituent at the nitrogen atom, and examples of the substituentinclude those mentioned as the substituent of N-mono-substitutedcarbamoyl group. The “N,N-di-substituted sulfamoyl group” is a sulfamoylgroup having two substituents at the nitrogen atom, and examples of thesubstituent include those mentioned as the substituent of theN,N-di-substituted carbamoyl group.

Examples of the “optionally esterified carboxyl group” include a freecarboxyl group as well as a lower alkoxycarbonyl group, anaryloxycarbonyl group, an aralkyloxycarbonyl group, etc.

Examples of the “lower alkoxycarbonyl group” include e.g. a C₁₋₆alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl,isopentyloxycarbonyl, neopentyloxycarbonyl, etc. Among them, a C₁₋₃alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, etc. is preferable.

Examples of the “aryloxycarbonyl group” include e.g. a C₇₋₁₂aryloxy-carbonyl group such as phenoxycarbonyl, 1-naphthoxycarbonyl,2-naphthoxycarbonyl, etc.

Examples of the “aralkyloxycarbonyl group” include e.g. a C₇₋₁₀aralkyloxy-carbonyl group, etc. (preferably, a C₆₋₁₀ aryl-C₁₋₄alkoxy-carbonyl, etc.) such as benzyloxycarbonyl, phenethyloxycarbonyl,etc.

The “aryloxycarbonyl group” and “aralkyloxycarbonyl group” may besubstituted. Examples of the substituent include the same kind andnumber of the substituents of the aryl group and aralkyl group asexamples of the substituent for the above described N-mono-substitutedcarbamoyl group.

Examples of the “acyl group derived from a sulfonic acid” as thesubstituent include a sulfonyl group substituted by a hydrocarbon group,and preferably include an acyl group such as C₁₋₁₀ alkyl-sulfonyl, C₂₋₆alkenyl-sulfonyl, C₂₋₆ alkynyl-sulfonyl, C₃₋₉ cyclo-alkyl-sulfonyl, C₃₋₉cyclo-alkenyl-sulfonyl, C₆₋₁₄ aryl-sulfonyl, C₇₋₁₀ aralkyl-sulfonyl etc.Examples of the C₁₋₁₀ alkyl include, for example, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, etc.Examples of the C₂₋₆ alkenyl include, for example, vinyl, allyl,1-propenyl, isopropenyl, 2-butenyl, 3-butenyl, 2-hexenyl, etc. Examplesof C₂₋₆ alkynyl include, for example, ethynyl, 2-propynyl, 2-butynyl,5-hexynyl, etc. Examples of the C₃₋₉ cyclo-alkyl include, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, etc.Examples of the C₃₋₉ cyclo-alkenyl include, for example,1-cyclopenten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl,3-cyclohexen-1-yl, 3-cycloocten-1-yl, etc. Examples of the C₆₋₁₄ arylinclude, for example, phenyl, 1-naphthyl, 2-naphthyl, etc. Examples ofthe C₇₋₁₀ aralkyl-sulfonyl include, for example, benzyl, phenethyl, etc.

These hydrocarbon groups bonded to the sulfonyl may be substituted.Examples of the substituent include, for example, hydroxyl, amino whichmay be substituted [the amino may be substituted with 1 or 2substituents. (examples of the substituent include lower alkyl group(e.g. C₁₋₆ alkyl etc. such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, t-butyl, pentyl, hexyl, etc.), an acyl group (e.g., C₁₋₆alkanoyl such as formyl, acetyl, propionyl, pivaloyl, etc., arylcarbonyl such as benzoyl, etc., C₁₋₆ alkyl-sulfonyl such asmethylsulfonyl, ethylsulfonyl, etc.)), halogen atom (for example,fluorine, chlorine, bromine, iodine, etc.), nitro group, cyano group,lower alkyl group which may be substituted by 1 to 5 halogen atom (forexample, fluorine, chlorine, bromine, iodine, etc.), lower alkyl groupwhich may be substituted by 1 to 5 halogen atom (for example, fluorine,chlorine, bromine, iodine, etc.) etc. Examples of the lower alkyl groupinclude, for example, C₁₋₆ alkyl group such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl,etc., and preferably include methyl, ethyl, etc. Examples of the loweralkoxy group include, for example, C₁₋₆ alkoxy group such as methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,tert-butoxy, etc, and preferably include methoxy, ethoxy, etc. Thesesubstituents may be the same or different from each other, and one, twoor three substituents, preferably one or two substituents may bepresent.

Examples of the “acyl group derived from a carboxylic acid” as thesubstituent include a carbonyl group having a hydrogen atom or onesubstituent which the above described “N-mono-substituted carbamoylgroup” have on the nitrogen atom, etc., preferably, a C₁₋₆ alkanoyl suchas formyl, acetyl, trifluoroacetyl, propionyl, butyryl, isobutyryl,pivaloyl, etc., an acyl of an aryl-carbonyl such as benzoyl etc.

Examples of the alkyl in “alkyl-sulfinyl group which may be substituted”as a substituent include a lower alkyl, for example, a C₁₋₆ alkyl suchas methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl,hexyl, etc. Examples of the aryl in “aryl-sulfinyl group which may besubstituted” as a substituent include, for example, a C₆₋₁₄ aryl groupetc., such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl,etc. Examples of the substituent of the alkyl group or the aryl groupinclude a lower alkoxy group (e.g. a C₁₋₆ alkoxy group etc, such asmethoxy, ethoxy, propoxy, etc.), a halogen atom (e.g., fluorine,chlorine, bromine, iodine, etc.), a lower alkyl group (a C₁₋₆ alkylgroup etc., such as methyl, ethyl, propyl, etc.), amino, hydroxyl,cyano, amidino, etc. One or two of these substituents may be present atany substitutable position.

Examples of “hydrocarbon group which may be substituted” and“non-aromatic heterocyclic group which may be substituted” shown asR^(a2) include the same ones as “hydrocarbon groups which may besubstituted” and “non-aromatic heterocyclic group which may besubstituted” shown by R^(a1), respectively. Among them, a C₂₋₆ alkylwhich may be substituted and a C₃₋₈ cycloalkyl which may be substitutedare preferable.

When R^(a1) and R^(a2) are bind to each other together with the adjacentnitrogen atom to form a heterocyclic ring group which may besubstituted, the heterocyclic ring contains one nitrogen atom, and mayfurther contain a nitrogen atom, an oxygen atom and a sulfur atom.Examples of the ring include, for example, a cyclic amino group such amonocyclic ring as 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl,1-homopiperidinyl, heptamethyleneimino, 1-piperazinyl,1-homopiperazinyl, 4-morpholinyl, 4-thiomorpholinyl, etc., such a fusedring as 2-isoindolinyl, 1,2,3,4-tetrahydro-2-isoquinolyl,1,2,4,5-tetrahydro-3H-3-benzoazepine-3-yl, etc., such a spiro ring asinden-1-spiro-4′-piperidin-1′-yl, etc. The cyclic amino group may have 1to 5 substituents, preferably 1 to 3 substituents at chemicallysubstitutable positions on the ring.

Examples of the substituent include a hydroxyl group, a cyano group, anitro group, an amino group, an oxo group, a halogen atom and a grouprepresented by the formula: —YR^(aa), wherein R^(aa) is a hydrocarbongroup which may be substituted or a heterocyclic group which may besubstituted, and Y is a bond (a single bond), —CR^(ab)R^(ac)—, —COO—,—CO—, —CR^(ab)(OH)—, —CO—NR^(ab)—, —CS—NR^(ab)—, —CO—S—, —CS—S—,—CO—NR^(ab)CO—NR^(ac)—, —C(═NH)—NR^(ab)—, —NR^(ab)—, —NR^(ab)—CO—,—NR^(ab)—CS—, —NR^(ab)—CO—NR^(ac)—, —NR^(ab)—CS—NR^(ac)—,—NR^(ab)—CO—O—, —NR^(ab)—, —NR^(ab)—CO—S—, —NR^(ab)—CS—S—,—NR^(ab)—C(═NH)—NR^(ac)—, —NR^(ab)—SO₂—, —NR^(ab)—NR^(ac)—, —O—, —O—CO—,—O—CS—, —O—CO—O, —O—CO—NR^(ab)—, —O—C(═NH)—NR^(ab), —S—, —SO—, —SO₂—,CR^(ab)R^(ac)—S—, CR^(ab)R^(ac)—SO₂—, —SO₂—NR^(ab)—, —S—CO—, —S—CS—,—S—CO—NR^(ab)—, —S—CS—NR^(ab), —S—C(═NH)—NR^(ab)—, wherein each ofR^(ab) and R^(ac) is a hydrogen atom, an alkyl group which may besubstituted, an alkenyl group which may be substituted, an alkynyl groupwhich may be substituted, an aryl group which may be substituted, acycloalkyl group which may be substituted, a cycloalkenyl group whichmay be substituted, a heterocyclic group which may be substituted, anacyl group derived from sulfonic acid, an acyl group derived fromcarboxylic acid, etc.

Examples of the “hydrocarbon group” in the “optionally substitutedhydrocarbon group” represented by R^(aa) include e.g. an aliphatichydrocarbon group, an alicyclic hydrocarbon group and an aryl group,etc. Examples of the aliphatic hydrocarbon group, the alicyclichydrocarbon group and the aryl group include those represented byR^(a1). Examples of the substituent of the “hydrocarbon group optionallysubstituted” include the same substituent as those in the abovedescribed “hydrocarbon group which may be substituted” represented byR^(a1).

Examples of the heterocyclic group in the “heterocyclic group which maybe substituted” represented by R^(aa) include the same heterocyclicgroup as those of “heterocyclic group which may be substituted”represented by R^(a3) mentioned below. Examples of the “substituent” inthe “heterocyclic group that may be substituted” include those mentionedas the “substituent” in a “non-aromatic heterocyclic group that may besubstituted” represented by R^(a1).

Examples of the “alkyl group which may be substituted”, “alkenyl groupwhich may be substituted”, “alkynyl group which may be substituted”,“aryl group which may be substituted”, “cyclo-alkyl group which may besubstituted”, “cyclo-alkenyl group which may be substituted”,“heterocyclic group which may be substituted”, “acyl group derived fromsulfonic acid”, and “acyl group derived from carboxylic acid”, each ofwhich is represented by R^(ab) and R^(ac), include those mentioned asthe substituent in the “hydrocarbon group which may be substituted”represented by R^(a1).

R^(a1) and R^(a2) preferably bind to each other together with thenitrogen atom to form a heterocyclic ring that may be substituted. Morepreferably, NR^(a1)R^(a2) is a group represented by the formula:

wherein Y^(a) and R^(aa) have the same meanings given above. In theabove, while Y^(a) and R^(aa) have the same meanings given above, R^(aa)is more preferably an aryl group which may be substituted or aheterocyclic group which may be substituted.

Examples of a “cyclic hydrocarbon group” in the “cyclic hydrocarbongroup which may be substituted” represented by R^(a3) include e.g. analicyclic hydrocarbon group, an aryl group, etc.

Examples of the “alicyclic hydrocarbon group” include e.g. a saturatedor unsaturated alicyclic hydrocarbon group such as a cycloalkyl group, acycloalkenyl group, a cycloalkanedienyl group, etc., preferably acycloalkyl group.

Examples of the “cycloalkyl group” include e.g. a C₃₋₉ cycloalkyl,(preferably a C₃₋₈ acycloalkyl, etc.) such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc., anda fused ring such as 1-indanyl, 2-indanyl, etc. Examples of the“cycloalkenyl group” include e.g. a C₃₋₆ cycloalkenyl group such as2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl,3-cyclohexen-1-yl, 1-cyclobuten-1-yl, 1-cyclopenten-1-yl, etc. Examplesof the “cycloalkanedienyl group” include e.g. a C₄₋₆ cycloalkanedienylgroup such as 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl,2,5-cyclohexadien-1-yl, etc.

Examples of the “aryl group” include e.g. a monocyclic or fusedpolycyclic aromatic hydrocarbon group. Among them, a C₆₋₁₄ aryl groupsuch as phenyl, naphthyl, anthryl, phenathryl, acenaphthyl, etc. ispreferable. In particular, phenyl, 1-naphthyl, 2-naphthyl, etc. arepreferable.

Examples of the substituent in the “cyclic hydrocarbon group which maybe substituted” represented by R^(a3) include those mentioned as thesubstituent in the “hydrocarbon group which may be substituted”represented by R^(a1). The substituent include, for example, a phenylgroup, a phenyl group which may be substituted by a C₁₋₆ alkyl groupsuch as a tolyl group, etc., a naphthyl group, etc., when the cyclichydrocarbon group is alicyclic hydrocarbon group, and is preferably, forexample a halogen atom (e.g., chlorine atom, fluorine atom, etc.), aC₁₋₆ alkyl group (methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, pentyl, hexyl, etc.), a C₁₋₆ alkoxy group (e.g., methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, etc.), a C₃₋₆ cyclo-alkyl group(e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), ahalogenated-C₁₋₆ alkyl group (trifluoromethyl, etc.), a halogenated-C₁₋₆alkoxy group (trifluoromethyloxy, etc.), a C₁₋₆ alkyl-thio group(methylthio, ethylthio, etc.), a C₁₋₆ alkyl-sulfonyl group(methylsulfonyl, ethylsulfonyl, etc.), cyano group, nitro group, etc.,when the cyclic hydrocarbon group is an aryl group.

Examples of the heterocyclic group in the “optionally substitutedheterocyclic group” represented by R^(a3) include e.g. an aromaticheterocyclic group, a saturated or unsaturated non-aromatic heterocyclicgroup (an alicyclic heterocyclic group) etc., which contains at leastone hetero-atom (preferably 1 to 4 hetero-atoms, more preferably 1 to 2hetero-atoms) consisting of 1 to 3 kinds of hetero-atoms (preferably 1to 2 kinds of hetero-atoms) selected from an oxygen atom, a sulfur atom,a nitrogen atom, etc. as atom(s) which form a ring (ring atoms).

Examples of the “aromatic heterocyclic group” include an aromaticmonocyclic heterocyclic group such as a 5- to 6-membered aromaticmonocyclic heterocyclic group, etc. (e.g. furyl, thienyl, pyrrolyl,oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, etc.); an aromatic fused heterocyclicgroup such as a 8- to 12-membered aromatic fused heterocyclic group(e.g. benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl,1H-indazolyl, benzindazolyl, benzoxazolyl, 1,2-benzoisooxazolyl,benzothiazolyl, benzopyranyl, 1,2-benzoisothiazolyl, benzodioxolyl,benxoimidazolyl, 2,1,1-benzoxadiazolyl, 1H-benzotriazolyl, quinolyl,isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl,naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl,β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl,phenazinyl, phenoxathinyl, thianthrenyl, phenanthridinyl,phenanthrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl,pyrazolo[1,5-a]pyridyl, pyrazolo[3,4-b]piridyl, imidazo[1,2-a]pyridyl,imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl,1,2,4-triazolo[4,3-b]pyridazinyl, etc.); etc., preferably, aheterocyclic group consisting of the above-mentioned 5- or 6-memberedaromatic monocyclic heterocyclic group fused with a benzene ring or aheterocyclic group consisting of the above-mentioned 5- or 6-memberedaromatic monocyclic heterocyclic group fused with the same or differentabove-mentioned 5- or 6-membered aromatic monocyclic heterocyclic group,etc.

Examples of the “non-aromatic heterocyclic group” include a 3- to8-membered (preferably 5- or 6-membered) saturated or unsaturated(preferably saturated) non-aromatic heterocyclic group (alicyclicheterocyclic group) such as oxiranyl, azetidinyl, oxetanyl, thiethanyl,pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidinyl,tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, etc.

Examples of the substituent in the “heterocyclic group which may besubstituted” represented by R^(a3) include those mentioned as thesubstituent “non-aromatic heterocyclic group which may be substituted”represented by R^(a1) R^(a3) is preferably a phenyl group that may besubstituted.

Examples of the “hydrocarbon group which may be substituted” representedby R^(a4) include the same “hydrocarbon group which may be substituted”represented by R^(a1). Examples of the “heterocyclic group which may besubstituted” represented by R^(a4) include the same “heterocyclic groupwhich may be substituted” represented by R^(a3).

Examples of the “alkoxy group” in “alkoxy group which may besubstituted” represented by R^(a4) preferably include, for example, aC₁₋₆ alkoxy such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec-butoxy, tert-butoxy, etc. Examples of the “substituent”include, for example, a cycloalkyl group (e.g. a C₃₋₆ cycloalkyl groupsuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), an arylgroup (e.g. a C₆₋₁₀ aryl group, etc., such as phenyl, 1-naphthyl,2-naphthyl, etc.), an aralkyl group (e.g. a C₇₋₁₀ aralkyl group forexample, such as benzyl, phenethyl, etc., preferably a phenyl-C₁₋₄ alkylgroup, etc.), a heterocyclic group (e.g., a “heterocyclic group”mentioned as the substituent in the “hydrocarbon group which may besubstituted” represented by R^(a1)), etc. Each of the lower alkyl group,the cycloalkyl group, the aryl group, the aralkyl group and theheterocyclic group may be substituted. Examples of the substituentsinclude, for example, a hydroxyl group, an amino group which may besubstituted [the amino group may have 1 or 2 substituents such as alower alkyl group (a C₁₋₆ alkyl group such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, etc.), an acyl group(a C₁₋₆ alkanoyl such as formyl, acetyl, propionyl, pivaloyl, etc., anaryl carbonyl such as benzoyl, etc. for example, a C₁₋₆ alkyl-sulfonyletc. such as methyl-sulfonyl, ethyl-sulfonyl etc.)], a halogen atom(e.g. fluorine, chlorine, bromine, iodine etc.), a nitro group, a cyanogroup, a lower alkyl group (which may be substituted by 1 to 5 halogenatoms (e.g. fluorine, chlorine, bromine, iodine etc.)), a lower alkoxygroup (which may be substituted by 1 to 5 halogen atoms (e.g. fluorine,chlorine, bromine, iodine etc.)), etc. Examples of the lower alkyl groupinclude a C₁₋₆ alkyl group such as methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc., and inparticular methyl, ethyl, etc. are preferable. Examples of the loweralkoxy group include, for example, a C₁₋₆ alkoxy group etc. such asmethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,tert-butoxy, etc., and in particular methoxy, ethoxy, etc. arepreferable. The above described lower alkoxy group may have 1 or 2 to 3(preferably 1 or 2) substituents. When the alkoxy group has 2 or 3substituents, these substituents may be the same or different.

Examples of the “aryl group” in “aryloxy group which may be substituted”represented by R^(a4) include, for example, a C₆₋₁₄ aryl group such asphenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, etc. Examplesof the substituent include, for example, a lower alkoxy group (e.g. aC₁₋₆ alkoxy group such as methoxy, ethoxy, propoxy, etc.), a halogenatom (e.g., fluorine, chlorine, bromine, iodine, etc.), a lower alkylgroup (for example a C₁₋₆ alkyl group such as methyl, ethyl, propyl,etc.), an amino group, a hydroxyl group, a cyano group, an amidinogroup, etc. These optional aryloxy groups may have 1 or 2 at anypossible position.

Examples of the “substituent” in “amino group which may be substituted”represented by R^(a4) include, for example, a lower alkyl group (e.g., aC₁₋₆ alkyl group such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, t-butyl, pentyl, hexyl, etc.), an acyl group (a C₁₋₆ alkanoyl(e.g., formyl, acetyl, propionyl, pivaloyl, etc.), benzoyl, etc.), aC₁₋₆ alkoxy-carbonyl which may be halogenated (e.g.,trifluoromethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl,trichloromethoxy carbonyl, 2,2,2-trichloroethoxy carbonyl, etc.), etc.In addition, the “amino group” in the “optionally substituted aminogroup” as the substituent may be substituted with an optionallysubstituted imidoyl group (e.g., a C₁₋₆ alkylimidoyl, formimidoyl,amidino, etc.), etc. and two substituents of the “amino group” may forma cyclic amino group together with a nitrogen atom. Examples of thecyclic amino group include e.g. a 3- to 8-membered (preferably 5- to6-membered) cyclic amino group such as 1-azetidinyl, 1-pyrrolidinyl,1-piperidinyl, 4-morpholinyl, 1-piperazinyl and 1-piperazinyl which mayhave at the 4-position a lower alkyl group (e.g. a C₁₋₆ alkyl group etc.such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl,etc.), an aralkyl group (e.g. a C₇₋₁₀ aralkyl group etc. such as benzyl,phenethyl, etc.), an aryl group (e.g. a C₆₋₁₀ aryl group etc. such asphenyl, 1-naphthyl, 2-naphthyl, etc.), etc.

R^(a4) is preferably a C₁₋₃ alkyl, a phenyl which may be substituted,3-pyridyl, 4-pyridyl, etc.

Examples of the hydrocarbon group represented by R^(a5) include thosementioned as a “hydrocarbon group” in the “hydrocarbon group that may besubstituted” represented by R^(a1). The preferable examples of thehydrocarbon group include a lower alkyl group having 1 to 4 carbon atomssuch as methyl, ethyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl,tert-butyl, etc.

Examples of the counter anion represented by Y^(a)— include, forexample, Cl⁻, Br⁻, I⁻, NO₃ ⁻, SO₄ ²⁻, PO₄ ³⁻, CH₃SO₃ ⁻, etc.

Examples of the divalent aliphatic hydrocarbon group in the divalentalipahatic hydrocarbon group which may be substituted by group otherthan an oxo group represented by E^(a) include, for example, a C₁₋₆alkylene such as methylene, ethylene, etc., a C₂₋₆ alkenylene such asethenylene, etc., a C₂₋₆ alkynylene such as ethynylen, etc., and amongthem, a C₂₋₅ alkylene is more preferable and trimethylene is the mostpreferable.

The substituent of the divalent hydrocarbon group is a substituent otherthan an oxo group, and examples of the substituents include, forexample, an alkyl group which may be substituted, an aryl group whichmay be substituted, a cycloalkyl group or a cycloalkenyl group which maybe substituted, a carboxyl group which may be esterified, a carbamoylgroup or a thiocarbamoyl group which may be substituted, an amino groupwhich may be substituted, a hydroxyl group which may be substituted, athiol (i.e. mercapto) group which may be substituted, an acyl groupderived from carboxylic acid, an acyl group derived from sulfonic acid,a halogen (e.g., fluorine, chlorine, bromine, etc.), nitro, cyano, etc.The divalent hydrocarbon group may have 1 to 3 substituents. Each of thealkyl group or the aryl group which may be substituted, the cycloalkylgroup or the cycloalkenyl group which may be substituted, the carboxylgroup which may be esterified, the carbamoyl group which may besubstituted, the thiocarbamoyl group which may be substituted, the aminogroup which may be substituted, the hydroxyl group which may besubstituted, the thiol group (i.e. mercapto group) which may besubstituted, the acyl group derived from carboxylic acid and the acylgroup derived from sulfonic acid include those mentioned as thesubstituent in “heterocyclic group which may be substituted” ofrepresented by R^(a3).

Examples of the C₁₋₃ aliphatic hydrocarbon group in “divalentC₁₋₃aliphatic hydrocarbon group which may be substituted” represented byQ^(a) and R^(a) inclde a divalent aliphatic hydrocarbon group having 1to 3 carbon atoms in the divalent aliphatic ydrocarbon group in divalentaliphatic hydrocarbon group which may be substituted by a group otherthan an oxo group represented by E^(a).

Examples of the substituent in the “divalent C₁₋₃ aliphatic ydrocarbongroup which may be substituted” represented by Q^(a) and R^(a) includethose mentioned as the substituent in divalent aliphatic ydrocarbongroup which may be substituted by a group other than an oxo grouprepresented by E^(a).

J^(a) is a methine or a nitrogen atom, and methine is preferable.

G^(a1) is a bond, CO or SO₂, and CO or SO₂ is preferable.

G^(a2) is CO, SO₂, NHCO, CONH or OCO, and among them, CO, NHCO and OCOare preferable.

The compound of the formula (I) or a salt thereof may be a hydrate.

The following compounds are preferable.

-   -   (I-1) A compound as shown in the above (1), wherein R^(a1) is a        hydrogen atom, a hydrocarbon group selected from Group a2 which        may be substituted by member(s) selected from Group a1, a 3- to        8-membered saturated or unsaturated non-aromatic heterocyclic        group which may be substituted by member(s) selected from Group        a1; R^(a2) is a hydrocarbon group selected from Group a2 which        may be substituted by member(s) selected from Group a1 or a 3-        to 8-membered saturated or unsaturated non-aromatic heterocyclic        group which may be substituted by member(s) selected from Group        a1, or R^(a1) and R^(a2) may combine each other together with        A^(a) to form a heterocyclic group selected from Group a4 which        may be substituted by member(s) selected from Group a3; A^(a) is        N or N⁺—R^(a5).Y^(a)— (Y^(a)— is Cl⁻, Br⁻, I⁻, NO₃ ⁻, SO₄ ²⁻,        PO₄ ³⁻ or CH₃SO₃ ⁻; R^(a5) is a hydrocarbon group selected from        Group a2); R^(a3) is a cyclic hydrocarbon group selected from        Group a5 which may be substituted by member(s) selected from        Group a1 or a heterocyclic group selected from Group a6 which        may be substituted by member(s) selected from Group a1; R^(a4)        is a hydrogen atom, a hydrocarbon group selected from Group a2        which may be substituted by member(s) selected from Group a1, a        heterocyclic group, selected from Group a6 which may be        substituted by member(s) selected from Group a1, a C₁₋₆ alkoxy        group which may be substituted by member(s) selected from Group        a7, a C₆₋₁₄ aryloxy group which may be substituted by member(s)        selected from Group a8, an amino group which may be substituted        by member(s) selected from Group a9 or a cyclic-amino group        selected from Group a10; E^(a) is a divalent aliphatic        hydrocarbon group selected from Group a12 which may be        substituted by member(s) other than oxo group(s) and selected        from Group a11; each of Q^(a) and R^(a) is a bond or a divalent        C₁₋₃ aliphatic ydrocarbon group selected from Group a13 which        may be substituted by member(s) selected from Group a11.        Group a1    -   (1) a C₁₋₆ alkyl group which may be substituted by member(s)        selected from Group a14, (2) a C₂₋₆ alkenyl group which may be        substituted by member(s) selected from Group a14, (3) a C₂₋₆        alkynyl group which may be substituted by member(s) selected        from Group a14, (4) a C₆₋₁₄ aryl group which may be substituted        by member(s) selected from Group a14, (5) a C₃₋₇ cycloalkyl        group which may be substituted by member(s) selected from Group        a14, (6) a C₃₋₆ cycloalkenyl group which may be substituted by        member(s) selected from Group a14, (7) a heterocyclic group        selected from Group a16 which may be substituted by member(s)        selected from Group a15, (8) an amino group which may be        substituted by a C₁₋₆ alkyl-imidoyl(s), formyl-imidoyl(s),        amidino(s) or member(s) selected from Group a17, (9) a        cyclic-amino group selected from Group a10, (10) an imidoyl        group which may be substituted by member(s) selected from Group        a17, (11) an amidino group which may be substituted by member(s)        selected from Group a17, (12) a hydroxyl group which may be        substituted by a member selected from Group a17, (13) a thiol        group which may be substituted by a member selected from Group        a17, (14) a carboxyl group, (15) a C₁₋₆ alkoxy-carbonyl group        which may be substituted by member(s) selected from Group        a18, (16) a C₇₋₁₂ aryloxy-carbonyl group which may be        substituted by member(s) selected from Group a18, (17) a C₇₋₁₀        aralkyl-oxy-carbonyl group which may be substituted by member(s)        selected from Group a18, (18) a carbamoyl group, (19) a        mono-substituted carbamoyl group which may be substituted by a        member selected from Group a19, (20) a di-substituted carbamoyl        group substituted by a member selected from Group a19 and a        member selected from Group a20, (21) a cyclic-aminocarbamoyl        group selected from Group a21, (22) a thiocarbamoyl group, (23)        a mono-substituted thiocarbamoyl group which may be substituted        by a member selected from Group a19, (24) a di-substituted        thiocarbamoyl group substituted by a member selected from Group        a19 and a member selected from Group a20, (25) a        cyclic-aminothiocarbamoyl group selected from Group a21, a        sulfamoyl group, (26) a N-mono-substituted sulfamoyl group        substituted by a member selected from Group a19, (27) a        N,N-di-substituted sulfamoyl group substituted by a member        selected from Group a19 and a member selected from Group        a20, (28) a cyclic-amino-sulfonyl group selected from Group        a22, (29) a halogen atom, (30) a cyano group, (31) a nitro        group, (32) an acyl group derived from a sulfonic acid selected        from Group a22, (33) a formyl group, (34) a C₂₋₆ alkanoyl        group, (35) a C₇₋₁₂ aryl-carbonyl group, (36) a C₁₋₆        alkyl-sulfinyl group which may be substituted by member(s)        selected from Group a23 and (37) a C₆₋₁₄ aryl-sulfinyl group        which may be substituted by member(s) selected from Group a23        Group a2    -   (1) a C₁₋₁₀ alkyl group, (2) a C₂₋₆ alkenyl group, (3) a C₂₋₆        alkynyl group, (4) a C₃₋₉ cycloalkyl group which may be        condensed with benzene, (5) a C₃₋₆ cycloalkenyl group, (6) a        C₄₋₆ cycloalkadienyl group and (7) a C₆₋₁₄ aryl group        Group a3    -   (1) a hydroxy group, (2) a cyano group, (3) a nitro group, (4)        an amino group, (5) an oxo group, (6) a halogen atom and (7) a        group represented by the formula:—B¹R^(aa) [wherein R^(aa) is a        hydrocarbon group selected from Group a2 which may be        substituted by member(s) selected from Group a1, or a        heterocyclic group selected from Group a6 which may be        substituted by member(s) selected from Group a1, B¹ is a bond (a        single bond), —CR^(ab)R^(aC)—, —COO—, —CO—, —CR^(ab)(OH)—,        —CR^(ab)R^(ac)—S—, —CR^(ab)R^(ac)—SO₂—, —CO—NR^(ab)—,        —CS—NR^(ab)—, —CO—S—, —CS—S—, —CO—NR^(ab)—CO—NR^(ac)—,        —C(═NH)—NR^(ab)—, —NR^(ab)—, —NR^(ab)—CO—, —NR^(ab)—CS—,        —NR^(ab)—CO—NR^(aC)—, —NR^(ab)—CS—NR^(aC)—, —NR^(ab)—CO—O—,        —NR^(ab)—CS—O—, —NR^(ab)—CO—S—, —NR^(ab)—CS—S—,        —NR^(ab)—C(═NH)—NR^(aC)—, —NR^(ab)—SO₂—, —NR^(ab)—NR^(aC)—, —O—,        —O—CO—, —O—CS—, —O—CO—O—, O—CO—NR^(ab)—, —O—C(═NH)—NR^(ab)—,        —S—, —SO—, —SO₂—, —SO₂—NR^(ab)—, —S—CO—, —S—CS—, —S—CO—NR^(ab)—,        —S—CS—NR^(ab)-and-S—C(═NH)—NR^(ab) (wherein each of R^(ab) and        R^(ac) is a hydrogen atom, a C₁₋₆ alkyl group which may be        substituted by member(s) selected from Group a14, a C₂₋₆ alkenyl        group which may be substituted by member(s) selected from Group        a14, a C₂₋₆ alkynyl group which may be substituted by member(s)        selected from Group a14, a C₆₋₁₄ aryl group which may be        substituted by member(s) selected from Group a14, a C₃₋₇        cycloalkyl group which may be substituted by member(s) selected        from Group a14, a C₃₋₆ cycloalkenyl group which may be        substituted by member(s) selected from Group a14, a heterocyclic        group selected from Group a6 which may be substituted by        member(s) selected from Group a1, an acyl group derived from a        sulfonic acid selected from Group a22, a C₁₋₆ alkanoyl, and a        C₇₋₁₂ aryl-carbonyl group)]        Group a4    -   (1) a monocyclic heterocyclic group, (2) a heterocyclic group        condensed with benzene and (3) a heterocyclic spiro compound,        each of which contains one nitrogen atom and may further contain        one or more atoms selected from the group consisting of a        nitrogen atom, a oxygen atom and a sulfur atom        Group a5    -   (1) a C₃₋₉ cycloalkyl which may be condensed with benzene, (2) a        C₃₋₆ cycloalkenyl group, (3) a C₄₋₆ cycloalkadienyl group        and (4) a C₆₋₁₄ aryl group        Group a6    -   (1) a 5- to 6-membered aromatic monocyclic heterocyclic group        selected from Group a24, (2) a 8- to 12-membered aromatic        condensed heterocyclic group selected from Group a26 and (3) a        3- to 8-membered saturated or unsaturated non-aromatic        heterocyclic group (aliphatic heterocyclic group) selected from        Group a25, each of which contains at least one hetero atom of        one to three hetero atoms selected from the group consisting of        an oxygen atom, a sulfur atom and a nitrogen atom etc. as a ring        formed of atoms (ring atoms).        Group a7    -   a C₃₋₆ cycloalkyl group which may be substituted by member(s)        selected from Group a18, a C₆₋₁₀ aryl group which may be        substituted by member(s) selected from Group a18, a C₇₋₁₀        aralkyl group which may be substituted by member(s) selected        from Group a18 and a heterocyclic group selected from Group a16        which may be substituted by member(s) selected from Group a18        Group a8    -   a C₁₋₆ alkoxy group, a halogen atom, a C₁₋₆ alkyl group, an        amino group, a hydroxyl group, a cyano group and an amidino        group        Group a9    -   (1) a C₁₋₆ alkyl group, (2) a C₁₋₆ alkanoyl, (3) benzoyl, (4) a        C₁₋₆ alkoxy-carbonyl which may be substituted by halogen(s), (5)        a C₁₋₆ alkyl-imidoyl, (6) formyl-imidoyl and (7) amidino        Group a10    -   (1) 1-azetidinyl, (2) 1-pyrrolidinyl, (3) 1-piperidinyl, (4)        4-morpholinyl and (5) a 1-piperazinyl which may be substituted        by member(s) selected from Group a27        Group a11    -   (1) a C₁₋₆ alkyl group which may be substituted by member(s)        selected from Group a14, (2) a C₆₋₁₄ aryl group which may be        substituted by member(s) selected from Group a14, (3) a C₃₋₇        cycloalkyl group which may be substituted by member(s) selected        from Group a14, (4) a C₃₋₆ cycloalkenyl group which may be        substituted by member(s) selected from Group a14, (5) a carboxyl        group, (6) a C₁₋₆ alkoxy-carbonyl group which may be substituted        by member(s) selected from Group a18, (7) a C₇₋₁₂        aryloxy-carbonyl group which may be substituted by member(s)        selected from Group a18, (8) a C₇₋₁₀ aralkyl-oxy-carbonyl group        which may be substituted by member(s) selected from Group        a18, (9) a carbamoyl group, (10) a mono-substituted carbamoyl        group substituted by a member selected from Group a19, (11) a        di-substituted carbamoyl group substituted by a member selected        from Group a19 and a member selected from Group a20, (12) a        cyclic-aminocarbamoyl group selected from Group a21, (13) a        thiocarbamoyl group, (14) a mono-substituted thiocarbamoyl group        substituted by a member selected from Group a19, (15) a        di-substituted thiocarbamoyl group substituted by a member        selected from Group a19 and a member selected from Group        a20, (16) a cyclic-aminothiocarbamoyl group selected from Group        a21, (17) an amino group which may be substituted by a C₁₋₆        alkyl-imidoyl(s), formyl-imidoyl(s), amidino(s) or member(s)        selected from Group a17, (18) a cyclic-amino group selected from        Group a10, (19) a hydroxyl group which may be substituted by a        member selected from Group a17, (20) a thiol group which may be        substituted by a member selected from Group a17, (21) a C₁₋₆        alkanoyl group, (22) a C₇₋₁₂ aryl-carbonyl group, (23) an acyl        group derived from a sulfonic acid selected from Group a22, (24)        a halogen, (25) nitro and (26) cyano        Group a12    -   a C₁₋₆ alkylene, a C₂₋₆ alkenylene and a C₂₋₆ alkynylene        Group a13    -   a C₁₋₃ alkylene, a C₂₋₃ alkenylene and a C₂₋₃ alkynylene        Group a14    -   (1) a C₁₋₆ alkoxy group which may be substituted by        halogen(s), (2) a phenoxy which may be substituted by halogen(s)        or carbamoyl(s), (3) a halogen atom, (4) a C₁₋₆ alkyl group, (5)        a C₁₋₄ alkyl group substituted by halogen(s), (6)C₃₋₈        cycloalkyl, (7) an amino group, (8) an amino group substituted        by one or two members selected from the group consisting of        carbamoyl, C₁₋₄ alkyl and C₁₋₄ alkyl-sulfonyl, (9) a carbamoyl        group which may be substituted by C₁₋₆ alkyl(s), (10)        formyl, (11) a C₂₋₆ alkanoyl group, (12) a C₆₋₁₄ aryl        group, (13) a C₆₋₁₄ aryl-carbonyl, (14) a C₇₋₁₃        aralkyl-carbonyl, (15) a hydroxyl group, (16) a C₂₋₅        alkanoyl-oxy, (17) a C₇₋₁₃ aralkyl-carbonyloxy, (18) a nitro        group, (19) a sulfamoyl group, (20) a N—C₁₋₄        alkyl-sulfamoyl, (21) a phenyl-thio, (22) a C₁₋₄        alkyl-phenylthio, (23) —N═N-phenyl, (24) a cyano group, (25) an        oxo group, (26) an amidino group, (27) a carboxyl group, (28) a        C₁₋₄ alkoxy-carbonyl group, (29) a C₁₋₆ alkyl-thio, (30) a C₁₋₆        alkyl-sulfinyl, (31) a C₁₋₆ alkyl-sulfonyl, (32) a C₆₋₁₄        aryl-thio, (33) a C₆₋₁₄ aryl-sulfinyl, (34) a C₆₋₁₄        aryl-sulfonyl and (35) a heterocyclic group selected from Group        a6        Group a15    -   a C₁₋₆ alkyl group, a C₁₋₆ alkanoyl, a C₇₋₁₃ aryl-carbonyl, a        C₁₋₆ alkyl-sulfonyl, an aminosulfonyl, a mono-C₁₋₆        alkyl-aminosulfonyl, a di-C₁₋₆ alkyl-aminosulfonyl and a C₁₋₄        alkyl group substituted by halogen        Group a16    -   (1) an aromatic heterocyclic group selected from Groups 24 and        26, and (2) a saturated or unsaturated non-aromatic heterocyclic        group selected from Group a25, each of which contains at least        one hetero atom of one to three hetero atoms selected from the        group consisting of an oxygen atom, a sulfur atom and a nitrogen        atom as ring constituting atom(s) (a ring atom)        Group a17    -   (1) a C₁₋₆ alkyl group which may be substituted by halogen or a        C₁₋₆ alkoxy, (2) a C₆₋₁₂ aryl group, (3) a C₆₋₁₂ aryl group        substituted by C₁₋₄ alkyl(s), (4) a C₃₋₈ cycloalkyl group which        may be substituted by halogen(s) or C₁₋₆ alkoxy(s), (5) a C₁₋₆        alkoxy group, (6) a C₁₋₆ alkanoyl, (7) a C₇₋₁₃        aryl-carbonyl, (8) a C₇₋₁₃ aryl-carbonyl substituted by C₁₋₄        alkyl(s), (9) a C₁₋₆ alkyl-sulfonyl, (10) a C₆₋₁₄        aryl-sulfonyl, (11) a aminosulfonyl, (12) a mono- or        di-substituted aminosulfonyl substituted by C₁₋₄ alkyl(s)        and (13) a C₁₋₆ alkoxy-carbonyl which may be substituted by        halogen(s)        Group a18    -   (1) a hydroxyl group, (2) an amino group, (3) a mono or        di-substituted amino group substituted by member(s) selected        from Group a28, (4) a halogen atom, (5) a nitro group, (6) a        cyano group, (7) a C₁₋₆ alkyl group which may be substituted by        halogen atom(s) and (8) a C₁₋₆ alkoxy group which may be        substituted by halogen atom(s)        Group a19    -   a C₁₋₆ alkyl group which may be substituted by member(s)        selected from Group a18, a C₃₋₆ cycloalkyl group which may be        substituted by member(s) selected from Group a18, a C₆₋₁₀ aryl        group which may be substituted by member(s) selected from Group        a18, a C₇₋₁₀ aralkyl group which may be substituted by member(s)        selected from Group a18, a C₁₋₆ alkoxy group which may be        substituted by member(s) selected from Group a18 and a        heterocyclic group selected from Group a16 which may be        substituted by member(s) selected from Group a18        Group a20    -   a C₁₋₆ alkyl group, a C₃₋₆ cycloalkyl group and a C₇₋₁₀ aralkyl        group        Group a21    -   a 1-azetidinyl-carbonyl, a 1-pyrrolidinyl-carbonyl, a        1-piperidinyl-carbonyl, a 4-morpholinyl-carbonyl and a        1-piperazinyl-carbonyl which may be substituted by member(s)        selected from Group a27        Group a22    -   a C₁₋₁₀ alkyl-sulfonyl which may be substituted by member(s)        selected from Group a18, a C₂₋₆ alkenyl-sulfonyl which may be        substituted by member(s) selected from Group a18, a C₂₋₆        alkynyl-sulfonyl which may be substituted by member(s) selected        from Group a18, a C₃₋₉ cycloalkyl-sulfonyl which may be        substituted by member(s) selected from Group a18, a C₃₋₉        cycloalkenyl-sulfonyl which may be substituted by member(s)        selected from Group a18, a C₆₋₁₄ aryl-sulfonyl which may be        substituted by member(s) selected from Group a18 and a C₇₋₁₀        aralkyl-sulfonyl group which may be substituted by member(s)        selected from Group a18        Group a23    -   a C₁₋₆ alkoxy group, a halogen atom, a C₁₋₆ alkyl group, an        amino group, a hydroxyl group, a cyano group and an amidino        group        Group a24    -   furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,        isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl,        1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,        1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,        1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl,        pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl        Group a25    -   oxylanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl,        tetrahydro furyl, thiolanyl, piperidinyl, tetrahydropyranyl,        morpholinyl, thiomorpholinyl and piperazinyl        Group a26    -   benzofuranyl, isobenzofuranyl, benzothienyl, indolyl,        isoindolyl, 1H-indazolyl, benzindazolyl, benzoxazolyl,        1,2-benzisoxazolyl, benzothiazolyl, benzopyranyl,        1,2-benzisothiazolyl, benzodioxolyl, benzimidazolyl,        2,1,1-benzoxadiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl,        cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl,        naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl,        β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl,        phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl,        phenanthridinyl, phenathrolinyl, indolizinyl,        pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl,        pyrazolo[3,4-b]pyridyl, imidazo[1,2-a]pyridyl,        imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,        imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl and        1,2,4-triazolo[4,3-b]pyridazinyl        Group a27    -   a C₁₋₆ alkyl group, a C₇₋₁₀ aralkyl group and a C₆₋₁₀ aryl group        Group a28    -   a C₁₋₆ alkyl group, a C₁₋₆ alkanoyl, a C₇₋₁₃ aryl-carbonyl and a        C₁₋₆ alkyl-sulfonyl    -   (I-2) a compound as shown in the above (I-1), wherein the 3- to        8-membered saturated or unsaturated nonaromatic heterocyclic        group which may be substituted by member(s) selected from Group        a1, represented by each of R^(a1) and R^(a2) is a 3- to        8-membered saturated or unsaturated nonaromatic heterocyclic        group selected from Group a25 which may be substituted by        member(s) selected from Group a1, and the heterocyclic group        selected from Group a4 which may be substituted by member(s)        selected from Group a3 formed by combining R^(a1) and R^(a2)        together with A^(a) is a cyclic-amino group selected from Group        a29 which may be substituted by member(s) selected from Group        a3.        Group a29    -   1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 1-homopiperidinyl,        heptamethylenimino, 1-piperazinyl, 1-homopiperazinyl,        4-morpholinyl, 4-thiomorpholinyl, 2-isoindolinyl,        1,2,3,4-tetrahydro-2-isoquinolyl,        1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl and        indene-1-spiro-4′-piperidine-1′-yl    -   (I-3) a compound as shown in the above (I-1) wherein R^(a1) and        R^(a2) combine each other together with A^(a) to form a 3- to        8-membered saturated or unsaturated non-aromatic heterocyclic        group selected from Group a4, which may be substituted by        member(s) selected from Group a3.    -   (I-4) a compound as shown in the above (I-1) wherein R^(a1) and        R^(a2) combine each other together with A^(a) to form a 3- to        8-membered saturated or unsaturated non-aromatic heterocyclic        group containing one or two nitrogen atoms, which ring may be        substituted by member(s) selected from Group a3.    -   (I-5) a compound as shown in the above (I-3), wherein the group        represented by -A^(a)R^(a1)R^(a2) is (1) a piperidinyl or (2) a        piperazinyl group, each of which may be substituted by member(s)        selected from Group a3.    -   (I-6) a compound as shown in the above (I-3), wherein the group        represented by -A^(a)R^(a1)R^(a2) is a group represented by the        formula:        wherein L^(a) is methine or a nitrogen atom, B^(a2) is a bond,        —CH₂—, —SO₂—, —SO—, —S—, —O—, —CO—, —NR^(ab1)—SO₂— (wherein        R^(ab1) is a hydrogen atom, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl        group, a C₂₋₆ alkynyl group, a C₃₋₆ cycloalkyl group), —CH(OH)—,        —NR^(ab2)— (wherein R^(ab2) is a hydrogen atom or a C₂₋₄        alkanoyl group), —NR^(ab1)—CO— (wherein R^(ab1) has the same        meaning given above), —NR^(ab1)—CO—O— (wherein R^(ab1) has the        same meaning given above), —CH₂SO₂— or —CH₂S—, R^(aa) is a        hydrocarbon group selected from Group a2 which may be        substituted by member(s) selected from Group a1 or a        heterocyclic group selected from Group a6 which may be        substituted by member(s) selected from Group a1.    -   (I-7) a compound as shown in the above (I-3), wherein the group        represented by the formula-A^(a)R^(a1)R^(a2) is a group        represented by the formula:        wherein B^(a3) is-CH₂—, —SO₂—, —SO—, —S—, —O—, —CO—,        —NR^(ab1)—SO₂— (wherein R^(ab1) is a hydrogen atom, a C₁₋₆₄        alkyl group, a C₂₋₆ alkenyl group, a C₂₋₆ alkynyl or a C₃₋₆        cycloalkyl group), —NR^(ab1)—CO—, —NR^(ab1)—CO—O— (wherein        NR^(ab1) has the same meaning given above), Z^(a) is a halogen,        SO₂NR^(ab3)R^(ab4) (wherein each of R^(ab3) and R^(ab4) is (1) a        C₁₋₆ alkyl which may be substituted by halogen(s), hydroxyl(s)        or C₁₋₆ alkoxy(s), (2) a C₃₋₈ cycloalkyl which may be        substituted by halogen(s) or C₁₋₆ alkoxy(s), (3) a C₁₋₆ alkoxy        or (4) a hydrogen atom or, R^(ab3) and R^(ab4) are combine each        other together with nitrogen to form a cyclic-amino group),        SO₂R^(ab5), (wherein R^(ab5) is (1) a C₁₋₆ alkyl group which may        be substituted by halogen(s), hydroxyl(s) or C₁₋₆ alkoxy(s), (2)        a C₃₋₈ cycloalkyl group which may be substituted by halogen(s)        or C₁₋₆ alkoxy(s)), a CONR^(ab3)R^(ab4) (wherein each of R^(ab3)        and R^(ab4) has the meaning given above) or —NR^(ab7)—SO₂R^(ab6)        (wherein R^(ab6) is (1) a C₁₋₆ alkyl group which may be        substituted by halogen(s) or C₁₋₆ alkoxy(s), (2) a C₃₋₈        cycloalkyl group which may be substituted by halogen(s) or C₁₋₆        alkoxy(s), R^(ab7) is (1) a C₁₋₆ alkyl group which may be        substituted by halogen(s) or C₁₋₆ alkoxy(s), (2) a C₃₋₈        cycloalkyl group which may be substituted by halogen(s) or C₁₋₆        alkoxy(s) or (3) a hydrogen atom), a C₁₋₆ alkoxy group, an amino        group which may be substituted by C₂₋₄ alkanoyl(s), nitro(s),        cyano(s), tetrazolyl(s) or morpholinyl(s).    -   (I-8) a compound as shown in the above (I-1), wherein R^(a3) is        a C₆₋₁₄ aryl group which may be substituted by member(s)        selected from Group a1.    -   (I-9) a compound as shown in the above (I-1), wherein R^(a3) is        a phenyl group which may be substituted by member(s) selected        from Group a1.    -   (I-10) a compound in which E^(a) is —CH₂CH₂—, —CH₂CH₂CH₂—,        —CH₂CH₂CH₂CH₂— or —CH₂CH₂CH₂CH₂CH₂—.    -   (I-11) a compound in which E^(a) is-CH₂CH₂CH₂—.    -   (I-12) a compound in which G^(a2) is CO, SO₂, CONH or OCO.    -   (I-13) a compound in which G^(a2) is CO or NHCO.    -   (I-14) a compound in which G^(a2) is CO.    -   (I-15) a compound in which J^(a) is methine.    -   (I-16) a compound in which G^(a1) is CO or SO₂.    -   (I-17) a compound as shown in the above (I-1), wherein R^(a4) is        a hydrocarbon group selected from Group a2 which may be        substituted by member(s) selected from Group a1, a heterocyclic        group selected from Group a6 which may be substituted by        member(s) selected from Group a1, a C₁₋₆ alkoxy group which may        be substituted by member(s) selected from Group a7, or an amino        group which may be substituted by member(s) selected from Group        a9.    -   (I-18) a compound in which R^(a4) is a C₁₋₃ alkyl.    -   (I-19) a compound in which R^(a4) is methyl.    -   (I-20) a compound in which each of Q^(a) and R^(a) is —CH₂CH₂—.    -   (I-21) a compound in which na is zero.    -   (I-22) a compound represented by the formula:        wherein R^(a4)a is (1) a C₁₋₆ alkyl group which may be        substituted by halogen(s), C₁₋₆ alkoxy(s), oxo(s), amino(s),        phenyl(s), pyridyl(s) or tetrazolyl(s), (2) a C₁₋₆ alkenyl        group, (3) a C₃₋₈ cycloalkyl group which may be substituted by        halogen(s), C₁₋₆ alkyl(s) or C₁₋₆ alkoxy(s), (4) a phenyl group        which may be substituted by halogen(s), C₁₋₆ alkyl(s), C₁₋₆        alkoxy(s), nitro(s), cyano(s), hydroxyl(s), C₁₋₄        alkanoyl-amino(s), carbamoyl(s) or sulfamoyl(s), (5) an amino        group which may be substituted by C₁₋₆ alkyl(s), (6) a C₁₋₆        alkoxy group which may be substituted by phenyl(s), (7) a C₃₋₈        cycloalkyl-oxy group (8) a heterocyclic group which may be        substituted by halogen(s), C₁₋₆ alkyl(s) or hydroxyl(s), G^(a1a)        is CO or SO₂, R^(a3a) is a C₆₋₁₀ aryl group which may be        substituted by (1) halogen(s), (2) C₁₋₆ alkyl(s) which may be        substituted by halogen(s), (3) C₁₋₆ alkoxy(s) which may be        substituted by halogen(s), (4) C₁₋₆ alkyl-thio(s), or (5) C₆₋₁₀        aryl group which may be substituted by C₁₋₆ alkyl-sulfonyl(s),        L^(a) is methine or a nitrogen atom, B^(a2) is a bond, —CH₂—,        —SO₂—, —SO—, —S—, —O—, —CO—, —NR^(ab1)—SO₂— (wherein R^(ab1) has        the same meaning given above), —CH(OH)—, —NR^(ab2) (wherein        R^(ab2) is a hydrogen atom or a C₂₋₄ alkanoyl group),        —NR^(ab1)—CO— (wherein R^(ab1) has the same meaning given        above), —NR^(ab1)—CO—O— (wherein R^(ab1) has the same meaning        given above), —CH₂SO₂— or —CH₂S—, R^(aa), is {circle over (1)}        an aromatic hydrocarbon group which may be substituted by        halogen(s), SO₂NR^(ab3)R^(ab4) (wherein each of R^(ab3) and        R^(ab4) has the same meaning given above), SO₂R^(ab5) (wherein        R^(ab5) is (1) a C₁₋₆ alkyl group which may be substituted by        halogen(s), hydroxyl(s) or C₁₋₆ alkoxy(s), (2) a C₃₋₈ cycloalkyl        group which may be substituted by halogen(s) or C₁₋₆ alkoxy(s)),        CONR^(ab3)R^(ab4) (wherein R^(ab3) and R^(ab4) have the same        meanings given above) or-NR^(ab7)—SO₂R^(ab6) (wherein R^(ab6)        has the same meaning given above), a C₁₋₆ alkoxy, an amino which        may be substituted by a C₂₋₄ alkanoyl(s), a nitro, a cyano, s        tetrazolyl or a morpholinyl or {circle over (2)} an aromatic        heterocyclic group which may be substituted by substituent(s)        selected from the above mentioned substituents of aromatic        hydrocarbon group, or salt thereof.    -   (I-23) a compound as shown in the above (I-22), wherein R^(a3a)        is a phenyl group which may be substituted by halogen(s),        trifluoromethyl(s) or C₁₋₆ alkyl(s).    -   (I-24) a compound as shown in the above (I-22), wherein L^(a) is        methine.    -   (I-25) a compound as shown in the above (I-22), wherein B^(a2)        is-CH₂—, —SO₂—, —SO—, —S—, —O—, —CO—, —NR^(ab1)—SO₂—,        —NR^(ab1)—CO— or NR^(ab1)—CO—O— (wherein R^(ab1) has the same        meaning given above).    -   (I-26) a compound as shown in the above (I-22), wherein R^(aa),        is a phenyl group which may be substituted by (1)        halogen(s), (2) SO₂R^(ae) (wherein R^(ae) is a C₁₋₆ alkyl group        or a C₃₋₈ cycloalkyl group), (3) N(R^(ad))SO₂R^(ae) (wherein        R^(ad) is a hydrogen atom or a C₁₋₄ alkyl group, R^(ae) has the        same meaning given above), (4) SO₂NR^(af)R^(ag) (wherein each of        R^(af) and R^(ag) is a hydrogen atom or a C₁₋₆ alkyl group or        R^(af) and R^(ag) may combine each other together with a        nitrogen atom to form a cyclic-amino group) or (5)        CONR^(af)R^(ag) (wherein R^(af) and R^(ag) are the same or        different and independently a hydrogen atom or a C₁₋₆ alkyl        group or, R^(af) and R^(ag) combine each other together with a        nitrogen atom to form a cyclic-amino group).    -   (I-27) a compound as shown in the above (I-22), wherein B² is        SO₂, CH₂ or N(R^(ad))—SO₂ (wherein R^(ad) is a hydrogen atom or        a C₁₋₄ alkyl); R^(aa′) is a phenyl which may be substituted        by (1) halogen(s), (2) SO₂R^(ae) (wherein R^(ae) is a C₁₋₆ alkyl        or a C₃₋₈ cycloalkyl), (3) N(R^(ad))SO₂R^(ae) (wherein R^(ad) is        a hydrogen atom or a C₁₋₄ alkyl, and R^(ae) has the same meaning        given above), (4) SO₂NR^(af)R^(ag) (wherein each of R^(af) and        R^(ag) is a hydrogen atom or a C₁₋₆ alkyl or R^(af) and R^(ag)        may combine each other together with a nitrogen atom to form a        cyclic-amino group) or (5) CONR^(af)R^(ag) (wherein each of        R^(af) and R^(ag) is a hydrogen atom or a C₁₋₆ alkyl group or        R^(af) and R^(ag) may combine each other together with a        nitrogen atom to form a cyclic-amino group); R^(a3a) is a phenyl        group substituted by one or two members selected from the group        of halogen atom and a C₁₋₄ alkyl.    -   (I-28) a compound as shown in the above (I-22), wherein G^(a1a)        is SO₂ or CO, L^(a) is methine, B^(a2) is SO₂ or CH₂, R^(aa), is        a group represented by the formula:        wherein Z^(a) is a C₁₋₄ alkyl-sulfonyl group, a sulfamoyl group        which may be substituted by a C₁₋₄ alkyl or a carbamoyl group;        R^(a3a) is a phenyl group which may be substituted by one or two        members selected from the group consisting of halogen atom(s) or        C₁₋₄ alkyl(s); and R^(a4a) is methyl.

Examples of the “hydrocarbon group” in the “a hydrocarbon group whichmay be substituted” represented by R^(b1) preferably include, forexample, an aliphatic chain hydrocarbon group, an alicyclic hydrocarbongroup and an aryl group etc. Examples of the aliphatic chain hydrocarbongroup include a C₁₋₆ alkyl group, for example, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl etc. Examples ofthe “alicyclic hydrocarbon group” preferably include a C₃₋₈ cycloalkylgroup such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, etc.

Examples of the aryl group preferably include a C₆₋₁₄ aryl group such asphenyl, naphthyl (1-naphthyl, 2-naphthyl), etc.

Examples of the “substituent(s)” in the “hydrocarbon group which may besubstituted” represented by R^(b1) include a hydrocarbon group which maybe substituted, a heterocyclic group which may be substituted, a halogenatom (e.g., fluorine, chlorine, bromine, iodine), a C₁₋₄ alkoxy groupwhich may be substituted, a C₁₋₄ alkylthio group which may besubstituted, a C₂₋₆ alkoxycarbonyl group which may be substituted, aC₁₋₆ alkanoyl group which may be substituted, an amino group which maybe substituted, a nitro group, a cyano group, a carbamoyl group whichmay be substituted, a sulfamoyl group which may be substituted, an acylgroup derived from a sulfonic acid, etc.

Examples of the “hydrocarbon group(s)” in the “hydrocarbon group whichmay be substituted” are those similar to the “hydrocarbon group” of the“hydrocarbon group which may be substituted”, which is represented byR^(b1). Among these substituents, a C₁₋₆ alkyl group, a C₃₋₈ cycloalkylgroup, a C₆₋₁₄ aryl group are preferred. These examples may include thesubstituents as mentioned above for R^(b1). Examples of the“substituents” in the “hydrocarbon group which may be substituted”include, for example, a lower alkoxy group (e.g., a C₁₋₆ alkoxy groupsuch as methoxy, ethoxy, propoxy, etc.), a halogen atom (e.g., fluorine,chlorine, bromine, iodine etc.), a lower alkyl group (e.g., a C₁₋₆ alkylgroup such as methyl, ethyl, propyl, etc.), a lower alkynyl group (e.g.,a C₁₋₄ alkynyl group such as vinyl, 1-propenyl, 2-propenyl, isopropenyl,butenyl, isobutenyl, etc.), an amino group, a hydroxy group, a cyanogroup, an amidino group etc. The hydrocarbon in “hydrocarbon that may besubstituted” may have 1 to 3 substituent(s) as described above at anypossible position. Examples of the heterocyclic group in the“heterocyclic group which may be substituted” (the substituent in the“hydrocarbon group which may be substituted, which is represented byR^(b1)”) include, for example, an aromatic heterocyclic group, saturatedor unsaturated non-aromatic heterocyclic group (alicyclic heterocyclicgroup) etc., which contains at least one heteroatom(s) (preferably 1 to4 heteroatom(s), more preferably, 1 to 2 heteroatom(s)) consisting of 1to 3 kind(s) of heteroatom(s) (preferably 1 to 2 kinds of heteroatom(s))selected from an oxygen atom, a sulfur atom, a nitrogen atom, etc. asring constituting atom(s).

Examples of the “aromatic heterocyclic group” include an aromaticmonocyclic heterocyclic group such as a 5 or 6-membered aromaticmonocyclic heterocyclic group (e.g., furyl, thienyl, pyrrolyl, oxazolyl,isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, etc.); an aromatic fused heterocyclicgroup such as a 8 to 12-membered aromatic fused heterocyclic group(e.g., benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl,1H-indazolyl, benzindazolyl, benzoxazolyl, 1,2-benzoisooxazolyl,benzothiazolyl, benzopyranyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl,quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl,phthalazinyl, naphthylidinyl, purinyl, pteridinyl, carbazolyl,α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl,phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl,phenanthridinyl, phenanthrolinyl, indolizinyl,pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl,imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl,1,2,4-triazolo[4,3-b]pyridazinyl, etc.); etc., preferably, aheterocyclic group consisting of the above-mentioned 5- or 6-memberedaromatic monocyclic heterocyclic group fused with a benzene ring orheterocyclic group consisting of the above-mentioned 5- or 6-memberedaromatic monocyclic heterocyclic group fused with the same or differentabove-mentioned 5- or 6-membered aromatic monocyclic heterocyclic group,etc.

Examples of the “non-aromatic heterocyclic group” include a 3 to8-membered (preferably 5 or 6-membered) saturated or unsaturated(preferably saturated) non-aromatic heterocyclic group (aliphaticheterocyclic group) such as oxiranyl, azetidinyl, oxetanyl, thiethanyl,pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidinyl,tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, etc.

Examples of the “substituent(s)” of the “heterocyclic group which may besubstituted” (substituent(s) of the hydrocarbon group which may besubstituted, which is represented by R^(b1)) are those similar to the“substituent(s)” of the “hydrocarbon group which may be substituted”that is (are) the “substituent(s)” of the hydrocarbon group which may besubstituted, which is represented by R^(b1).

Examples of “C₁₋₄ alkoxy group” in the “C₁₋₄ alkoxy group which may besubstituted” include, for example, methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc. Example of “C₁₋₄ analkylthio group” in the “C₁₋₄ an alkylthio group which may besubstituted” include, for example, methylthio, ethylthio, n-propylthio,isopropylthio, n-butylthio, isobutylthio, tert-butylthio, etc. Exampleof the “C₂₋₆ alkoxycarbonyl group” in “C₂₋₆ alkoxycarbonyl group whichmay be substituted” include, for example, methoxycarbonyl,ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl,isobutoxycarbonyl, tert-butoxycarbonyl, n-pentyloxycarbonyl, etc.

Examples of the “C₁₋₆ alkanoyl group” in the “C₁₋₆ alkanoyl group whichmay be substituted” include, for example, formyl, acetyl, propionyl,pivaloyl etc. Examples of the substituent in the “C₁₋₄ alkoxy groupwhich may be substituted”, “C₁₋₄ alkylthio group which may besubstituted”, and “C₁₋₆ alkoxycarbonyl group which may be substituted”,“C₁₋₆ alkanoyl group which may be substituted” are those similar to thesubstituent(s) of the “hydrocarbon group which may be substituted”,which are the substituent(s) of the “hydrocarbon group which may besubstituted” represented by R^(b1).

Examples of the substituent(s) of the “amino group which may besubstituted” include, for example, a lower alkyl group (e.g., a C₁₋₆alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, pentyl, hexyl, etc.), an acyl group derived from a carboxylicacid (e.g., a C₁₋₆ alkanoyl such as formyl, acetyl, propionyl, pivaloyl,etc.), a C₇₋₁₅ arylcarbonyl such as benzoyl, etc., an acyl group derivedfrom a sulfonic acid (e.g., a C₁₋₆ alkylsulfonyl such as methylsulfonyl,ethylsulfonyl, etc.), an optionally halogenated C₂₋₆ alkoxycarbonyl(e.g., trifluoromethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl,trichloromethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, etc.), etc. Inaddition, the “amino group” in the “amino group that may be substituted”may be substituted with an imidoyl group that may be substituted (e.g.,a C₁₋₆ alkylimidoyl, formylimidoyl, amidino, etc.), etc. Alternatively,two substituents of the amino group may form a cyclic amino grouptogether with a nitrogen atom. Examples of the cyclic amino groupinclude e.g. 3 to 8-membered (preferably 5 or 6-membered) cyclic aminogroup such as 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl,4-morpholinyl, 1-piperazinyl and 1-piperazinyl which may have at the4-position a lower alkyl group (e.g., a C₁₋₆ alkyl group such as methyl,ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, etc.), anaralkyl group (e.g. a C₇₋₁₀ aralkyl group such as benzyl, phenethyl,etc.), an aryl group (e.g. a C₆₋₁₀ aryl group such as phenyl,1-naphthyl, 2-naphthyl, etc.), etc.

Examples of the “carbamoyl group which may be substituted” includeunsubstituted carbamoyl, a N-mono-substituted carbamoyl group and aN,N-di-substituted carbamoyl group.

The “N-mono-substituted carbamoyl group” is a carbamoyl group having onesubstituent on the nitrogen atom and the substituent include, forexample, a lower alkyl group (e.g., a C₁₋₆ alkyl group such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl,etc.), a cycloalkyl group (e.g., a C₃₋₆ cycloalkyl group such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), an aryl group(e.g., a C₆₋₁₀ aryl group such as phenyl, 1-naphthyl, 2-naphthyl, etc.),an aralkyl group (e.g., a C₇₋₁₀ aralkyl group, preferably a phenyl-C₁₋₄alkyl group such as benzyl, phenethyl, etc.), a heterocyclic group(e.g., the above described “heterocyclic group” as the substituent ofthe “hydrocarbon group which may be substituted” represented by R^(b1),etc.), etc. The lower alkyl group, the cycloalkyl group, the aryl group,the aralkyl group and the heterocyclic group as described above may havesubstituent(s), and the substituent(s) include, for example, a hydroxygroup, an amino group which may be substituted [the amino group may have1 or 2 substituent(s) (e.g. a lower alkyl group (e.g., a C₁₋₆ alkylgroup such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, pentyl, hexyl, etc.), an acyl group (e.g., a C₁₋₆ alkanoyl suchas formyl, acetyl, propionyl, pivaloyl, etc., an arylcarbonyl such asbenzoyl, etc., a C₁₋₆ alkylsulfonyl such as methylsulfonyl,ethylsulfonyl, etc.), etc.)], a halogen atom (e.g., fluorine, chlorine,bromine, iodine, etc.), a nitro group, a cyano group, a lower alkylgroup which may be substituted with 1 to 5 halogen atom(s) (e.g.,fluorine, chlorine, bromine, iodine, etc.), a lower alkoxy group whichmay be substituted with 1 to 5 halogen atom(s) (e.g., fluorine,chlorine, bromine, iodine, etc.), etc. The lower alkyl group includes,e.g. a C₁₋₆ alkyl group such as methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. and inparticular methyl, ethyl, etc. are preferable. The lower alkoxy groupinclude e.g. a C₁₋₆ alkoxy group such as methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc. and inparticular methoxy, ethoxy, etc. are preferable. The above describedlower alkyl group, cycloalkyl group, aryl group, aralkyl group andheterocyclic group may have 1, 2 or 3 (preferably 1 or 2)substituent(s).

The “N,N-di-substituted carbamoyl group” is a carbamoyl group having twosubstituents on the nitrogen atom. Examples of one of the substituentsinclude the same as those of the above described “N-mono-substitutedcarbamoyl group” and examples of the other substituent include e.g. alower alkyl group (e.g., a C₁₋₆ alkyl group such as methyl, ethyl,propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, etc.), a C₃₋₆cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, etc.), a C₇₋₁₀ aralkyl group (e.g., benzyl, phenethyl, etc.,preferably phenyl-C₁₋₄ alkyl group, etc.), etc. In addition, twosubstituents of the “N,N-di-substituted carbamoyl group” may form acyclic amino group together with a nitrogen atom. Examples of the cyclicaminocarbonyl group include, e.g., 3 to 8-membered (preferably 5 or6-membered) cyclic aminocarbonyl group such as 1-azetidinylcarbonyl,1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, 4-morpholinylcarbonyl,1-piperazinylcarbonyl and 1-piperazinylcarbonyl which may have a loweralkyl group (e.g., a C₁₋₆ alkyl group such as methyl, ethyl, propyl,isopropyl, butyl, t-butyl, pentyl, hexyl, etc.), an aralkyl group (e.g.,a C₇₋₁₀ aralkyl group such as benzyl, phenethyl, etc.), an aryl group(e.g., a C₆₋₁₀ aryl group such as phenyl, 1-naphthyl, 2-naphthyl, etc.),etc. at the 4-position.

Examples of the “sulfamoyl group which may be substituted” include anunsubstituted sulfamoyl group, a N-mono-substituted sulfamoyl group anda N,N-di-substituted sulfamoyl group.

The “N-mono-substituted sulfamoyl group” is a sulfamoyl group having onesubstituent at the nitrogen atom, and examples of the substituentinclude those mentioned for the substituents of N-mono-substitutedcarbamoyl group.

The “N,N-di-substituted sulfamoyl group” is a sulfamoyl group having twosubstituents at the nitrogen atom, and examples of the substituentsinclude those mentioned as the substituents of the N,N-di-substitutedcarbamoyl group.

Examples of the “acyl group derived from a sulfonic acid” include asulfonyl group substituted by a hydrocarbon group, and preferably,include an acyl group such as C₁₋₁₀ alkylsulfonyl, C₂₋₆ alkenylsulfonyl,C₂₋₆ alkynylsulfonyl, C₃₋₉ cycloalkylsulfonyl, C₃₋₉cycloalkenylsulfonyl, C₆₋₁₄ arylsulfonyl, C₇₋₁₀ aralkylsulfonyl.Examples of the C₁₋₁₀ alkyl include, for example, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, etc.Examples of the C₂₋₆ alkenyl include, for example, vinyl, allyl,1-propenyl, isopropenyl, 2-butenyl, 3-butenyl, 2-hexenyl, etc. Examplesof C₂₋₆ alkynyl include, for example, ethynyl, 2-propynyl, 2-butynyl,5-hexynyl, etc. Examples of the C₃₋₉ cycloalkyl include, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, etc.Examples of the C₃₋₉ cycloalkenyl include, for example,1-cyclopenten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl,3-cyclohexen-1-yl, 3-cycloocten-1-yl, etc. Examples of the C₆₋₁₄ arylinclude, for example, phenyl, 1-naphthyl, 2-naphthyl, etc. Examples ofthe C₇₋₁₀ aralkyl-sulfonyl include, for example, benzyl, phenethyl, etc.These hydrocarbon groups that are the substituents of the sulfonyl maybe substituted. Examples of these substituents include, for example,hydroxy group, amino group which may be substituted [the amino group maybe substituted by one or two lower alkyl group (e.g., C₁₋₆ alkyl such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl,hexyl, etc.), an acyl group (e.g., a C₁₋₆ alkanoyl such as formyl,acetyl, propionyl, pivaloyl, etc., an aryl carbonyl such as benzoyl,etc., a C₁₋₆ alkylsulfonyl such as methylsulfonyl, ethylsulfonyl,etc.)], a halogen atom (for example, fluorine, chlorine, bromine,iodine, etc.), nitro group, cyano group, a lower alkyl which may besubstituted by 1 to 5 halogen atom(s) (e.g. fluorine, chlorine, bromine,iodine, etc.), a lower alkoxy group which may be substituted by 1 to 5halogen atom(s) (e.g. fluorine, chlorine, bromine, iodine, etc.).Examples of the lower alkyl group include, for example, a C₁₋₆ alkylgroup such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, etc., and preferably includemethyl, ethyl, etc. The lower alkoxy group includes, for example, a C₁₋₆alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec-butoxy, tert-butoxy, etc, and preferably includesmethoxy, ethoxy, etc. Preferably, one, two or three (preferably one ortwo) from these substituents are used, wherein the substituents may bethe same or different. Examples of the “cyclic hydrocarbon group” in the“cyclic hydrocarbon group which may be substituted” represented byR^(b2) include alicyclic hydrocarbon group and aryl group.

Examples of the “alicyclic hydrocarbon group” include, for example, asaturated or unsaturated alicyclic hydrocarbon group such as acycloalkyl group, a cycloalkenyl group, a cycloalkanedienyl group, etc.Examples of the “cycloalkyl group” include, for example, a C₃₋₉cycloalkyl (preferably, a C₃₋₈ cycloalkyl etc.) such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclononyl, etc., and a fused ring such as 1-indanyl, 2-indanyl, etc.Examples of the “cycloalkenyl group” include, for example, a C₃₋₆cycloalkenyl group such as 2-cyclopenten-1-yl, 3-cyclopenten-1-yl,2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 1-cyclobuten-1-yl,1-cyclopenten-1-yl, etc. Examples of the “cycloalkanedienyl group”include, for example, a C₄₋₆ cycloalkanedienyl group such as2,4-cyclopentanedien-1-yl, 2,4-cyclohexanedien-1-yl,2,5-cyclohexanedien-1-yl, etc. In particular, a C₃₋₈ cyrloalkyl groupsuch as cyclohexyl is preferable.

Examples of the “aryl group” include a monocyclic or fused polycyclicaromatic hydrocarbon group. Among others, a C₆₋₁₄ aryl group such asphenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, 4-indanyl,5-indanyl, etc. is preferable. In particular, phenyl, 1-naphthyl,2-naphthyl, etc. are preferable.

Examples of the “substituent(s)” in the “cyclic hydrocarbon group whichmay be substituted” represented by R^(b2) are those similar to the“substituent” of the “hydrocarbon group which may be substituted”described as the substituent(s) of the “hydrocarbon group which may besubstituted”, which are represented by R^(b1).

Examples of the “heterocyclic group which may be substituted” of R^(b2)are those similar to the “heterocyclic group which may be substituted”described as the substituent(s) of the “hydrocarbon group which may besubstituted”, which are represented by R^(b1).

The halogen atom represented by R^(b3) includes, for example, fluorine,chlorine, bromine, iodine, etc.

The “carbamoyl group which may be substituted”, “sulfamoyl group whichmay be substituted” and “acyl group derived from a sulfonic acid”represented by R^(b3) are those similar to the “carbamoyl group whichmay be substituted”, “sulfamoyl group which may be substituted” and“acyl group derived from a sulfonic acid”, which are represented byR^(b1). Examples of the “C₁₋₄ alkyl group” of the “C₁₋₄ alkyl groupwhich may be substituted” represented by R^(b3) include, for example,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl.Examples of the “C₁₋₄ alkoxy group” of the “C₁₋₄ alkoxy group which maybe substituted” represented R^(b3) include, for example, methoxy,ethoxy, propoxy, n-butoxy, isobutoxy, tert-butoxy.

Example of the substituent(s) in the “C₁₋₄ alkyl group which may besubstituted” and “C₁₋₄ alkoxy group which may be substituted”, which isrepresented by R^(b3) are those similar to the “substituent(s)” of the“hydrocarbon group which may be substituted” which is (are) the“substituent(s)” of “the hydrocarbon group which may be substituted”,which is represented by R^(b1).

Examples of the substituents of “amino group which may be substituted”represented by R^(b3) include, for example, a lower alkyl group (e.g.,C₁₋₆ alkyl group such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, t-butyl, pentyl, hexyl, etc.), an acyl group derived fromcarboxylic acid (e.g., C₁₋₆ alkanoyl such as formyl, acetyl, propionyl,pivaloyl, etc.), for example, C₇₋₁₅ arylcarbonyl such as benzoyl, etc,an acyl group derived from sulfonic acid (e.g., C₁₋₆ alkylsulfonyl suchas methylsulfonyl, ethylsulfonyl, etc.), an optionally halogenated C₁₋₆alkoxy-carbonyl (e.g., trifluoromethoxycarbonyl,2,2,2-trifluoroethoxycarbonyl, trichloromethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, etc.), etc. In addition, the “aminogroup” of the “amino group that may be substituted” may be substitutedwith an imidoyl group that may be substituted (e.g., a C₁₋₆alkylimidoyl, formylimidoyl, amidino, etc.), etc. and two substituentsof the “amino group” may form a cyclic amino group together with anitrogen atom. Examples of the cyclic amino group include, for example,3 to 8-membered (preferably, 5 or 6-membered) cyclic amino group such as1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl,1-piperazinyl and 1-piperazinyl which may have a lower alkyl group(e.g., a C₁₋₆ alkyl group such as methyl, ethyl, propyl, isopropyl,butyl, t-butyl, pentyl, hexyl, etc.), an aralkyl group (e.g., a C₇₋₁₀aralkyl group such as benzyl, phenethyl, etc.), an aryl group (e.g., aC₆₋₁₀ aryl group such as phenyl, 1-naphthyl, 2-naphthyl, etc.), etc. atthe 4-position.

Examples of the leaving group represented by X include, for example, ahalogen atom (e.g., a chlorine atom, a bromine atom, an iodine atom,etc.), an alkyl or aryl sulfonyloxy group (e.g., methanesulfonyloxy,trifluoromethanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy,p-toluenesulfonyloxy, etc.), etc.

Examples of the salt of a compound of the formula (II) of the presentinvention include a salt with an acid, for example, a salt withinorganic acid (e.g., hydrochloric acid salt, sulfuric acid salt,hydrobromic acid salt, phosphoric acid salt, etc.), a salt of an organicacid (e.g., acetic acid salt, trifluoroacetic acid salt, succinic acidsalt, maleic acid salt, fumaric acid salt, propionic acid salt, citricacid salt, tartaric acid salt, lactic acid salt, oxalic acid salt,methanesulfonic acid salt, p-toluenesulfonic acid salt, etc.), etc., asalt with a base (e.g., an alkali metal salt such as potassium salt,sodium salt, lithium salt, etc., an alkaline earth metal salt such ascalcium salt, magnesium salt, etc., ammonium salt, a salt with anorganic base such as ammonium salt, trimethylamine salt, triethylaminesalt, tert-butyl dimethyl amine salt, dibenzyl methylamine salt, benzyldimethylamine salt, N,N-dimethylaniline salt, pyridine salt, quinolinesalt, etc.).

The compound of the formula (II) or salt thereof may also be hydrated.Hereinafter the compound of the formula (II), its salt and its hydrateare referred to as Compound (II).

Among the compounds represented by the formula (II) or salts thereof(hereinafter referred to as Compounds (II)), the following compounds arepreferable.

-   -   (II-1) the compound wherein R^(b3) is a halogen atom, a C₁₋₄        alkyl group which may be substituted, a C₁₋₄ alkoxy group which        may be substituted, an amino group which may be substituted, a        nitro group or a cyano group,    -   (II-2) the compound wherein R^(b1) is an alicyclic hydrocarbon        group which may be substituted or an aryl group which may be        substituted,    -   (II-3) the compound wherein R^(b1) is a hydrocarbon group which        may be substituted by 1 to 4 substituent(s) selected from 1) a        hydrocarbon group which may be substituted, 2) an heterocyclic        group which may be substituted, 3) a C₁₋₄ alkoxy group which may        be substituted, 4) a C₁₋₄ alkylthio group which may be        substituted, 5) a C₂₋₆ alkoxycarbonyl group which may be        substituted, 6) a C₁₋₆ alkanoyl group which may be        substituted, 7) an amino group which may be substituted, 8) a        cyclic amino group, 9) a halogen atom, 10) a nitro group, 11) a        cyano group, 12) a carbamoyl group which may be substituted, 13)        a sulfamoyl group which may be substituted and 14) an acyl group        derived from a sulfonic acid,    -   (II-4) the compound wherein R^(b1) is a hydrocarbon group which        may be substituted by 1 to 4 substituent(s) selected from 1) a        hydrocarbon group which may be substituted, 2) a heterocyclic        group which may be substituted, 3) a C₁₋₄ alkoxy group which may        be substituted, 4) a C₁₋₄ alkylthio group which may be        substituted, 5) a C₂₋₆ alkoxycarbonyl group which may be        substituted, 6) an amino group which may be substituted, 7) a        halogen atom, 8) a nitro group and 9) a cyano group,    -   (II-5) the compound wherein R^(b1) is a hydrocarbon group which        may be substituted by 1 to 4 substituent(s) selected from 1) a        hydrocarbon group which may be substituted, 2) a heterocyclic        group which may be substituted, 3) a C₁₋₄ alkylthio group which        may be substituted, 4) a C₂₋₆ alkoxycarbonyl group which may be        substituted, 5) an amino group which may be substituted, 6) a        halogen atom and 7) a nitro group,    -   (II-6) the compound wherein R^(b2) is an cyclic hydrocarbon        group which may be substituted,    -   (II-7) the compound wherein R^(b3) is a halogen, a carbamoyl        group which may be substituted, a sulfamoyl group which may be        substituted or an acyl group derived from a sulfonic acid,    -   (II-8) the compound wherein R^(b3) is a halogen,    -   (II-9) the compound wherein R^(b4) is a hydrogen atom,    -   (II-10) the compound wherein n is 0,    -   (II-11) the compound wherein R^(b1) is a hydrocarbon group        selected from Group 3 which may be substituted by member(s)        selected from Group 1; R^(b2) is a cyclic hydrocarbon group        selected from Group 10 which may be substituted by member(s)        selected from Group 2, or a heterocyclic group selected from        Group 4 which may be substituted by member(s) selected from        Group 2; R^(b3) is a halogen atom, a carbamoyl group, a        N-mono-substituted carbamoyl group which may be substituted by a        member selected from Group 11, a N,N-di-substituted carbamoyl        group which may be substituted by a member selected from Group        11 and a member selected from Group 14, a cyclic aminocarbonyl        group selected from Group 17, a sulfamoyl group,        N-mono-substituted sulfamoyl group which may be substituted by a        member selected from Group 11, a N,N-di-substituted sulfamoyl        group which may be substituted by a member selected from Group        11 and a member selected from Group 14, a cyclic aminosulfonyl        group selected from Group 20, an acyl group derived from a        sulfonic acid selected from Group 15, a C₁₋₄ alkyl group which        may be substituted by member(s) selected from Group 2, a C₁₋₄        alkoxy group which may be substituted by member(s) selected from        Group 2, an amino group which may be substituted by member(s)        selected from Group 8, a cyclic amino group selected from Group        9, a nitro group or a cyano group.        Group 1    -   1) a hydrocarbon group selected from Group 3 which may be        substituted by member(s) selected from Group 2, 2) a        heterocyclic group selected from Group 4 which may be        substituted by member(s) selected from Group 2, 3) a C₁₋₄ alkoxy        group which may be substituted by member(s) selected from Group        2, 4) a C₁₋₄ alkylthio group which may be substituted by        member(s) selected from Group 2, 5) a C₂₋₆ alkoxycarbonyl group        which may be substituted by member(s) selected from Group 2, 6)        a C₁₋₆ alkanoyl group, 7) an amino group which may be        substituted by member(s) selected from Group 8, 8) a cyclic        amino group selected from Group 9, 9) a halogen atom, 10) a        nitro group, 11) a cyano group, 12) a carbamoyl group, 13) a        mono-substituted carbamoyl group which is substituted by a        member selected from Group 11, 14) di-substituted carbamoyl        group which is substituted by a member selected from Group 11        and a member selected Group 14, 15) a cyclic amino carbamoyl        group selected from Group 17, 16) a sulfamoyl group, 17) a        N-mono substituted sulfamoyl group which is substituted by a        member selected from Group 11, 18) a N,N-di-substituted        sulfamoyl group which is substituted by a member selected from        Group 11 and a member selected Group 14, 19) an acyl group        derived from a sulfonic acid selected from Group 19        Group 2    -   1) a C₁₋₆ alkoxy group, 2) a halogen atom, 3) a C₁₋₆ alkyl        group, 4) a C₁₋₄ alkynyl group, 5) an amino group, 6) a hydroxy        group, 7) a cyano group and 8) an amidino group        Group 3    -   1) a C₁₋₆ alkyl group, 2) a C₃₋₈ cycloalkyl group and 3) a C₆₋₁₄        aryl group        Group 4    -   1) an aromatic monocyclic heterocyclic group selected from Group        5, 2) an aromatic condensed heterocyclic group selected from        Group 6 and 3) a saturated or unsaturated non-aromatic        heterocyclic group selected from Group 7        Group 5    -   furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,        isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl,        1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,        1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,        1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl,        pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl        Group 6    -   benzofuranyl, isobenzofuranyl, benzothienyl, indolyl,        isoindolyl, 1H-indazolyl, benzindazolyl, benzoxazolyl,        1,2-benzisoxazolyl, benzothiazolyl, benzopyranyl,        1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl,        cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl,        naphthylidinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl,        β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl,        phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl,        phenanthridinyl, phenathrolinyl, indolizinyl,        pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl,        imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl,        imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl,        1,2,4-triazolo[4,3-a]pyridyl and        1,2,4-triazolo[4,3-b]pyridazinyl        Group 7    -   oxylanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl,        tetrahydrofuryl, thiolanyl, piperidinyl, tetrahydropyranyl,        morpholinyl, thiomorpholinyl and piperazinyl        Group 8    -   1) a C₁₋₆ alkyl, 2) a C₁₋₆ alkanoyl, 3) a C₇₋₁₃ arylcarbonyl, 4)        an optionally halogenated C₂₋₆ alkoxycarbonyl, 5) a C₁₋₆        alkylimidoyl, 6) a formylimidoyl and 7) an amidino        Group 9    -   1) 1-azetidinyl, 2) 1-pyrrolidinyl, 3) 1-piperidinyl, 4)        4-morpholinyl, 5) 1-piperazinyl and 6) 1-piperazinyl which may        have a C₁₋₆ alkyl, a C₇₋₁₀ aralkyl and a C₆₋₁₀ aryl at        4-position        Group 10    -   C₃₋₉ cycloalkyl, 1-indanyl, 2-indanyl, C₃₋₆ cycloalkenyl, C₄₋₆        cycloalkanedienyl and C₆₋₁₄ aryl        Group 11    -   1) a C₁₋₆ alkyl group which may be substituted by member(s)        selected from Group 12, 2) a C₃₋₆ cycloalkyl group which may be        substituted by member(s) selected from Group 12, 3) a C₆₋₁₀ aryl        group which may be substituted by member(s) selected from Group        12, 4) a C₇₋₁₀ aralkyl group which may be substituted by        member(s) selected from Group 12, 5) a C₁₋₆ alkoxy group which        may be substituted by member(s) selected from Group 12 and 6) a        heterocyclic group selected from Group 13 which may be        substituted by member(s) selected from Group 12        Group 12    -   1) a hydroxy group, 2) an amino group, 3) an amino group which        is mono or di-substituted by member(s) selected from Group        16, 4) a halogen atom, 5) a nitro group, 6) a cyano group, 7) a        C₁₋₆ alkyl group which may be substituted by halogen atom(s)        and 8) a C₁₋₆ alkoxy group which may be substituted by halogen        atom(s)        Group 13    -   1) an aromatic heterocyclic group selected from Group 5 and        Group 6 and 2) a saturated or unsaturated non-aromatic        heterocyclic group selected from Group 7, each of which contains        at least one heteroatom(s) selected from the group consisting of        an oxygen atom, a sulfur atom and a nitrogen atom as        ring-constituting atom(s)        Group 14    -   a C₁₋₆ alkyl group, a C₃₋₆ cycloalkyl group and a C₇₋₁₀ aralkyl        group        Group 15    -   1) a C₁₋₁₀ alkylsulfonyl which may be substituted by member(s)        selected from Group 12, 2) a C₂₋₆ alkenylsulfonyl which may be        substituted by member(s) selected from Group 12, 3) a C₂₋₆        alkynylsulfonyl which may be substituted by member(s) selected        from Group 12, 4) a C₃₋₉ cycloalkylsulfonyl which may be        substituted by member(s) selected from Group 12, 5) a C₃₋₉        cycloalkenylsulfonyl which may be substituted by member(s)        selected from Group 12, 6) a C₆₋₁₄ arylsulfonyl which may be        substituted by member(s) selected from Group 12 and 7) a C₇₋₁₀        aralkylsulfonyl which may be substituted by member(s) selected        from Group 12        Group 16    -   a C₁₋₆ alkyl group, a C₁₋₆ alkanoyl, a C₇₋₁₃ arylcarbonyl and a        C₁₋₆ alkylsulfonyl        Group 17    -   1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl,        1-piperidinylcarbonyl, 4-morpholinylcarbonyl and        1-piperazinylcarbonyl which may be substituted by member(s)        selected from Group 18        Group 18    -   a C₁₋₆ alkyl group, a C₇₋₁₀ aralkyl group and a C₆₋₁₀ aryl group        Group 19    -   a C₁₋₁₀ alkylsulfonyl which may be substituted by member(s)        selected from Group 12, a C₂₋₆ alkenylsulfonyl which may be        substituted by member(s) selected from Group 12, a C₂₋₆        alkynylsulfonyl which may be substituted by member(s) selected        from Group 12, a C₃₋₉ cycloalkylsulfonyl which may be        substituted by member(s) selected from Group 12, a C₃₋₉        cycloalkenylsulfonyl which may be substituted by member(s)        selected from Group 12, a C₆₋₁₄ arylsulfonyl which may be        substituted by member(s) selected from Group 12, and a C₇₋₁₀        aralkylsulfonyl which may be substituted by member(s) selected        from Group 12        Group 20    -   1-azetidinylsulfonyl, 1-pyrrolidinylsulfonyl,        1-piperidinylsulfonyl, 4-morpholinylsulfonyl and        1-piperazinylsulfonyl which may be substituted by member(s)        selected from Group 18    -   (II-12) the compound wherein R^(b1) is a C₃₋₈ cycloalkyl group        which may be substituted by member(s) selected from Group 1 or a        C₆₋₁₄ aryl group which may be substituted by member(s) selected        from Group 1,    -   (II-13) the compound as shown in the above (II-12), wherein        R^(b1) is 1) a C₆₋₁₄ aryl group which may be substituted by a        halogen atom, a C₁₋₆ alkyl which may be substituted by        halogen(s), a C₁₋₄ alkylthio, a nitro, a carbamoyl, a sulfamoyl        or a C₁₋₆ alkylsulfonyl, 2) a C₁₋₆ alkyl group which may be        substituted by (i) a C₂₋₆ alkoxycarbonyl group or (ii) a phenyl        which may be substituted by C₁₋₆ alkyl(s) or 3) a C₃₋₈        cycloalkyl group which may be substituted by (i) a halogen        atom, (ii) a C₁₋₆ alkyl(s) which may be substituted by        halogen(s) or (iii) a C₁₋₆ alkoxy group which may be substituted        by halogen(s);    -   R^(b2) is a phenyl group which may be substituted by a halogen        atom, a C₁₋₆ alkyl, a C₁₋₄ alkoxy or a cyano, a C₃₋₈ cycloalkyl        group or a pyridyl group;    -   R^(b3) is (i) a halogen atom, (ii) a carbamoyl group, (iii) a        sulfamoyl group which may have one or two C₁₋₆ alkyl(s) or C₃₋₆        cycloalkyl(s) at N-atoms, a cyclic aminosulfonyl group selected        from Group 20, a C₁₋₆ alkylsulfonyl group or C₃₋₆        cycloalkylsulfonyl group;    -   R^(b4) is a hydrogen atom;    -   nb is 0 or 1 and    -   pb is 0 or 1,    -   (II-14) the compound as shown in the above (II-12), wherein        R^(b1) is 1) a phenyl which may be substituted by a halogen        atom, a C₁₋₃ alkyl, trifluoromethyl, methoxy, trifluoromethoxy,        methylthio or nitro, 2) a naphthyl, 3) a C₁₋₆ alkyl group which        may be substituted by (i) a C₂₋₃ alkoxycarbonyl, (ii) phenyl        or (iii) 3-isopropenylphenyl or 4) cyclohexyl group;    -   R^(b2) is a phenyl group which may be substituted by a halogen        atom, methyl, methoxy or cyano, a cyclohexyl group or a        3-pyridyl group;    -   R^(b3) is (i) a halogen atom, (ii) a carbamoyl group, (iii) a        4-morpholinylsulfonyl group or (iv) a methylsulfonyl group,    -   R^(b4) is a hydrogen atom;    -   nb is 0 or 1; and    -   pb is 0 or 1,    -   (II-15) the compound as shown in the above (II-12), wherein        R^(b1) is a phenyl group which may be substituted by a halogen        atom or a C₁₋₃ alkyl; R^(b2) is a phenyl group which may be        substituted by a halogen atom and methyl(s);        R^(b3) is (i) a halogen atom, (ii) a carbamoyl group, (iii) a        sulfamoyl group which may be substituted by one or two members        selected from the group consisting of C₁₋₆ alkyl and C₃₋₆        cycloalkyl at N-atoms, a cyclic aminosulfonyl group selected        from Group 20, a C₁₋₆ alkylsulfonyl group or a C₃₋₆ cycloalkyl        sulfonyl group, R^(b4) is a hydrogen atom, nb is 0, and pb is 0        or 1.

The hydrocarbon group represented by R^(c1) includes, for example, analiphatic chain hydrocarbon group, an alicyclic hydrocarbon group, anaryl group and the like. Preferably, it is an aliphatic chainhydrocarbon group or an alicyclic hydrocarbon group.

The aliphatic chain hydrocarbon group includes, for example, a straightor branched aliphatic hydrocarbon group such as alkyl group, alkenylgroup, alkynyl group and the like, with preference given to alkyl group.Examples of the alkyl group include C₁₋₁₀ alkyl groups (preferably C₁₋₆alkyl etc.), such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl,1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl,3,3-dimethylbutyl, 3,3-dimethylpropyl, 2-ethylbutyl, n-heptyl,1-methylheptyl, 1-ethylhexyl, n-octyl, 1-methylheptyl, nonyl and thelike.

Examples of the alkenyl group include C₂₋₆ alkenyl groups, such asvinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl,2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 4-hexenyl, 5-hexenyl and the like. Examples of the alkynylgroup include C₂₋₆ alkynyl groups, such as ethynyl, 1-propynyl,2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl,3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl,5-hexynyl and the like.

Examples of the alicyclic hydrocarbon group include saturated orunsaturated alicyclic hydrocarbon groups, such as cycloalkyl group,cycloalkenyl group, cycloalkanedienyl group and the like, withpreference given to cycloalkyl group. Examples of the cycloalkyl groupinclude C₃₋₉ cycloalkyl (preferably C₃₋₈ cycloalkyl etc.), such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl and the like, and fused rings such as 1-indanyl,2-indanyl and the like.

Examples of the cycloalkenyl group include C₃₋₆ cycloalkenyl groups,such as 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl,3-cyclohexen-1-yl, 1-cyclobuten-1-yl, 1-cyclopenten-1-yl and the like.

Examples of the cycloalkanedienyl group include C₄₋₆ cycloalkanedienylgroups, such as 2,4-cyclopentanedien-1-yl, 2,4-cyclohexanedien-1-yl,2,5-cyclohexanedien-1-yl and the like.

Examples of the aryl group include monocyclic or fused polycyclicaromatic hydrocarbon groups, which are preferably C₆₋₁₄ aryl groups,such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl,4-indanyl, 5-indanyl etc., and the like, with particular preferencegiven to phenyl, 1-naphthyl, 2-naphthyl and the like.

The hydrocarbon group having 2 or more carbon atoms represented byR^(c2) includes, for example, the hydrocarbon groups having 2 or morecarbon atoms among those represented by R^(c1). Of those recited withregard to R^(c1), preferred are C₂₋₆ alkyl and C₃₋₈ cycloalkyl.

When R^(c1) and R^(c2) in combination form, together with an adjacentnitrogen atom, a ring optionally having a substituent or substituents,the ring may contain, besides one nitrogen atom, a different nitrogenatom, an oxygen atom and a sulfur atom. Examples thereof includemonocyclic groups, such as 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl,1-homopiperidinyl, heptamethyleneimino, 1-piperazinyl,1-homopiperazinyl, morpholino, thiomorpholino and the like, fused ringssuch as 2-isoindolinyl, 1,2,3,4-tetrahydro-2-isoquinolyl,1,2,4,5-tetrahydro-3H-3-benzodiazepin-3-yl and the like, cyclic aminogroups such as spiro ring and the like (e.g.,indene-1-spiro-4′-piperidin-1′-yl etc.), the cyclic amino groupoptionally having 1 to 5, preferably 1 to 3, substituent(s) at achemically permitted position on the ring.

Examples of the substituent include hydroxy group, cyano group, nitrogroup, oxo group, halogen atom (e.g., fluorine atom, chlorine atom,bromine atom, iodine atom etc.), a group of the formula: —Y^(c)R^(ca)(wherein R^(ca) is a hydrocarbon group optionally having a substituentor substituents or a heterocyclic group optionally having a substituentor substituents, Y^(c) is a bond (single bond), —CR^(cb)R^(cc)—, —COO—,—CO—, —CO—NR^(cb)—, —CS—NR^(cb)—, —CO—S—, —CS—S—,—CO—NR^(cb)CO—NR^(cc)—, —C(═NH)—NR^(cb)—, —NR^(b)—, —NR^(cb)—CO—,—NR^(cb)—CS—, —NR^(cb)—CO—NR^(cc)—, —NR^(cb)—CS—NR^(cc)—,—NR^(cb)—CO—O—, —NR^(cb)—CS—O—, —NR^(cb)—SO₂—, —NR^(cb)—NR^(cc)—, —O—,—O—CO—, —O—CS—, —O—CO—O, —O—CO—NR^(cb)—, —O—C(═NH)—NR^(cb)—, —S—, —SO—,—SO₂—, —SO₂—NR^(cb), —S—CO—, —S—CS—, —S—CO—NR^(cb)—, —S—CS—NR^(cb)—,—S—C(═NH)—NR^(cb)— and the like, wherein R^(cb) and R^(cc) are each ahydrogen atom, alkyl group optionally having a substituent orsubstituents, alkenyl group optionally having a substituent orsubstituents, alkynyl group optionally having a substituent orsubstituents, an aryl group optionally having a substituent orsubstituents, cycloalkyl group or cycloalkenyl group optionally having asubstituent or substituents, a heterocyclic group optionally having asubstituent or substituents, acyl group derived from carboxylic acid,alkylsulfonyl group optionally having a substituent or substituents, anaryl sulfonyl group optionally having a substituent or substituents,etc.), and the like.

The “hydrocarbon group” of the hydrocarbon group optionally having asubstituent or substituents represented by R^(ca) includes an aliphaticchain hydrocarbon group, alicyclic hydrocarbon group, aryl group and thelike.

Examples of these aliphatic chain hydrocarbon group, alicyclichydrocarbon group and aryl group is the aliphatic chain hydrocarbongroup, alicyclic hydrocarbon group and aryl group represented by R^(c1)respectively. Examples of the substituent of the hydrocarbon groupinclude those mentioned as the substituents for the “hydrocarbon groupoptionally having a substituent or substituents” represented by R^(c3)to be mentioned later.

Examples of the “heterocyclic group optionally having a substituent orsubstituents” at the aforementioned R^(ca) include those mentioned asthe “heterocyclic group optionally having a substituent or substituents”represented by R^(c3) to be mentioned later.

Examples of the alkyl group optionally having a substituent orsubstituents, alkenyl group optionally having a substituent orsubstituents, alkynyl group optionally having a substituent orsubstituents, aryl group optionally having a substituent orsubstituents, cycloalkyl group or cycloalkenyl group optionally having asubstituent or substituents, heterocyclic group optionally having asubstituent or substituents, acyl group derived from carboxylic acid,alkyl sulfonyl group optionally having a substituent or substituents andarylsulfonyl group optionally having a substituent or substituents,represented by the aforementioned R^(cb) and R^(cc) include thosementioned as the substituent of the hydrocarbon group optionally havinga substituent represented by R^(c3) to be mentioned later.

It is preferable that R^(c1) and R^(c2) in combination forms, togetherwith an adjacent nitrogen atom, a heterocyclic ring optionally having asubstituent or substituents. More preferably, NR^(c1)R^(c2) is a groupof the formula:

-   -   wherein Y^(c) and R^(ca) are as defined above. As used here,        Y^(c) and R^(ca) are as defined above, and R^(ca) is        particularly preferably an aryl group optionally having a        substituent or substituents or a heterocyclic group optionally        having a substituent or substituents.

Y^(c)R^(ca) is particularly preferably a benzyl group optionally havinga substituent or substituents.

NR^(c1)R^(c2) is particularly preferably a 4-benzyl-1-piperidinyl groupoptionally having a substituent or substituents.

Examples of the hydrocarbon group of the hydrocarbon group optionallyhaving a substituent or substituents represented by R^(c3) include thosesimilar to the hydrocarbon groups represented by R^(c1), with particularpreference given to C₁₋₆ alkyl group, C₃₋₈ cycloalkyl group and arylgroup. These are exemplified by those recited for R^(c1).

The heterocyclic group of the heterocyclic group optionally having asubstituent or substituents represented by R^(c3) is, for example, anaromatic heterocyclic group, a saturated or unsaturated non-aromaticheterocyclic group (aliphatic heterocyclic group) and the like,containing, as an atom constituting the ring system, at least one(preferably 1 to 4, more preferably 1 or 2) of 1 to 3 kinds (preferably1 or 2 kinds) of the hetero atom selected from an oxygen atom, a sulfuratom, a nitrogen atom and the like.

Examples of the aromatic heterocyclic group include aromatic monocyclicheterocyclic group (e.g., 5- or 6-membered aromatic monocyclicheterocyclic group such as furyl, thienyl, pyrrolyl, oxazolyl,isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl etc.); condensed aromatic heterocyclicgroup [e.g., 8 to 12-membered condensed aromatic heterocyclic group(preferably a heterocycle wherein the aforementioned 5- or 6-memberedaromatic monocyclic heterocyclic group is condensed with a benzene ringor a heterocycle wherein the same or different two heterocycles of theaforementioned 5- or 6-membered aromatic monocyclic heterocyclic groupare condensed), such as benzofuranyl, isobenzofuranyl, benzothienyl,indolyl, isoindolyl, 1H-indazolyl, benzindazolyl, benzooxazolyl,1,2-benzoisooxazolyl, benzothiazolyl, benzopyranyl,1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl,cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl,purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl,γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl,phenoxathiinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl,indolizinyl, pyrro[1,2-b]pyridazinyl, pyrrazolo[1,5-a]pyridyl,imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl,1,2,4-triazolo[4,3-b]pyridazinyl etc.] and the like.

Examples of the non-aromatic heterocyclic group include 3 to 8-membered(preferably 5- or 6-membered) saturated or unsaturated (preferablysaturated) non-aromatic heterocyclic group (aliphatic heterocyclicgroup), such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl,tetrahydrofuryl, thioranyl, piperidinyl, tetrahydropyranyl, morpholinyl,thiomorpholinyl, piperazinyl etc., and the like.

Examples of the substituent of the hydrocarbon group optionally having asubstituent or substituents as represented by R^(c3) and the substituentof the heterocyclic group optionally having a substituent orsubstituents as represented by R^(c3) include alkyl group optionallyhaving a substituent or substituents, alkenyl group optionally having asubstituent or substituents, alkynyl group optionally having asubstituent or substituents, an aryl group optionally having asubstituent or substituents, cycloalkyl group or cycloalkenyl groupoptionally having a substituent or substituents, a heterocyclic groupoptionally having a substituent or substituents, amino group optionallyhaving a substituent or substituents, imidoyl group optionally having asubstituent or substituents, amidino group optionally having asubstituent or substituents, hydroxy group optionally having asubstituent or substituents, thiol group optionally having a substituentor substituents, optionally esterified carboxyl group, carbamoyl groupoptionally having a substituent or substituents, thiocarbamoyl groupoptionally having a substituent or substituents, sulfamoyl groupoptionally having a substituent or substituents, halogen atom (e.g.,fluorine, chlorine, bromine, iodine etc., preferably chlorine, bromineetc.), cyano group, nitro group, acyl group derived from carboxylicacid, alkyl sulfinyl group optionally having a substituent orsubstituents, alkyl sulfonyl group optionally having a substituent orsubstituents, arylsulfinyl group optionally having a substituent orsubstituents, arylsulfonyl group optionally having a substituent orsubstituents and the like, wherein 1 to 5 (preferably 1 to 3) of theseoptional substituents may be present at a substitutable position.

The aryl group of the “aryl group optionally having a substituent orsubstituents” as a substituent may be, for example, C₆₋₁₄ aryl groupsuch as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl etc.,and the like. Here, the substituent of the aryl group includes, forexample, lower alkoxy group (e.g., C₁₋₆ alkoxy group such as methoxy,ethoxy, propoxy etc., and the like), halogen atom (e.g., fluorine,chlorine, bromine, iodine etc.), lower alkyl group (e.g., C₁₋₆ alkylgroup such as methyl, ethyl, propyl etc., etc.), amino group, hydroxygroup, cyano group, amidino group and the like, wherein one or two ofthese optional substituents may be present at a substitutable position.

The cycloalkyl group of the “cycloalkyl group optionally having asubstituent or substituents” as a substituent may be, for example, C₃₋₇cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl etc., and the like. As used herein, examples ofthe substituent of the “cycloalkyl group” are similar in the kind andthe number to those exemplified for the substituent of theaforementioned “aryl group optionally having a substituent orsubstituents”.

The cycloalkenyl group of the “cycloalkenyl group optionally havingsubstituents” as a substituent may be, for example, C₃₋₆ cycloalkenylgroup such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyletc., and the like. As used herein, examples of the substituent of the“cycloalkenyl group optionally having a substituent or substituents” aresimilar in the kind and the number to those exemplified for thesubstituent of the aforementioned “aryl group optionally having asubstituent or substituents”.

The alkyl group of the “alkyl group optionally having a substituent orsubstituents” as a substituent may be, for example, C₁₋₆ alkyl such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n-hexyl,isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl,3,3-dimethylpropyl etc., and the like. As used herein, examples of thesubstituent of the alkyl group are similar in the kind and the number tothose exemplified for the substituent of the aforementioned “aryl groupoptionally having a substituent or substituents”.

The alkenyl group of the “alkenyl group optionally having a substituentor substituents” as a substituent may be, for example, C₂₋₆ alkenylgroup such as vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl,2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 4-hexenyl, 5-hexenyl etc., and the like. As used herein,examples of the substituent of the alkenyl group are similar in the kindand the number to those exemplified for the substituent of theaforementioned “aryl group optionally having a substituent orsubstituents”.

The alkynyl group of the “alkynyl group optionally having a substituentor substituents” as a substituent may be, for example, C₂₋₆ alkynylgroup, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl,2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like. As used herein,examples of the substituent of the alkynyl group are similar in the kindand the number to those exemplified for the substituent of theaforementioned “aryl group optionally having a substituent orsubstituents”.

The heterocyclic group of the “heterocyclic group optionally having asubstituent or substituents” as a substituent may be, for example, anaromatic heterocyclic group, a saturated or unsaturated non-aromaticheterocyclic group (aliphatic heterocyclic group) and the like,containing, as an atom (cyclic atom) constituting the ring system, atleast one (preferably 1 to 4, more preferably 1 or 2) of 1 to 3 kinds(preferably 1 or 2 kinds) of the hetero atom selected from an oxygenatom, a sulfur atom and a nitrogen atom, and the like.

Examples of the “aromatic heterocyclic group” include aromaticmonocyclic heterocyclic group (e.g., 5- or 6-membered aromaticmonocyclic heterocyclic group, such as furyl, thienyl, pyrrolyl,oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl etc.) and condensed aromaticheterocyclic group [e.g., 8 to 12-membered condensed aromaticheterocycle (preferably a heterocycle wherein the aforementioned 5- or6-membered aromatic monocyclic heterocyclic group is condensed with abenzene ring or a heterocycle wherein the same or different twoheterocycle of the aforementioned 5- or 6-membered aromatic monocyclicheterocyclic group are condensed), such as benzofuranyl,isobenzofuranyl, benzothienyl, indolyl, isoindolyl, 1H-indazolyl,benzindazolyl, benzooxazolyl, 1,2-benzoisooxazolyl, benzothiazolyl,1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl,cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl,purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl,γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl,phenoxathiinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl,indolizinyl, pyrro[1,2-b]pyridazinyl, pyrrazolo[1,5-a]pyridyl,imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl,1,2,4-triazolo[4,3-b]pyridazinyl etc.] and the like.

Examples of the “non-aromatic heterocyclic group” include 3 to8-membered (preferably 5- or 6-membered) saturated or unsaturated(preferably saturated) non-aromatic heterocyclic group (aliphaticheterocyclic group), such as oxiranyl, azetidinyl, oxetanyl, thietanyl,pyrrolidinyl, tetrahydrofuryl, thioranyl, piperidinyl,tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl etc., andthe like.

The substituent that the “heterocyclic group optionally having asubstituent or substituents” as a substituent may have is exemplified bylower alkyl group (e.g., C₁₋₆ alkyl group, such as methyl, ethyl, propyletc., and the like), acyl group (e.g., C₁₋₆ alkanoyl, such as formyl,acetyl, propionyl, pivaloyl etc., benzoyl etc.), and the like.

The substituent of the “amino group optionally having a substituent orsubstituents”, “imidoyl group optionally having a substituent orsubstituents”, “amidino group optionally having a substituent orsubstituents”, “hydroxy group optionally having a substituent orsubstituents” and “thiol group optionally having a substituent orsubstituents” as a substituent may be, for example, lower alkyl group(e.g., C₁₋₆ alkyl group, such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, t-butyl, pentyl, hexyl etc., and the like), acyl group(e.g., C₁₋₆ alkanoyl (e.g., formyl, acetyl, propionyl, pivaloyl etc.),benzoyl etc.), C₁₋₆ alkyl sulfonyl (e.g., methanesulfonyl,ethanesulfonyl etc.), C₃₋₁₄ arylsulfonyl (e.g., benzenesulfonyl,p-toluenesulfonyl etc.), optionally halogenated C₁₋₆ alkoxy-carbonyl(e.g., trifluoromethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl,trichloromethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl etc.), and thelike. The “amino group” of the “amino group optionally having asubstituent or substituents” as the substituent may be substituted byimidoyl group optionally having a substituent or substituents (e.g.,C₁₋₆ alkyl imidoyl, formylimidoyl, amidino etc.), and the like. Inaddition, two substituents may form a cyclic amino group together with anitrogen atom. In this case, examples of the cyclic amino group include3 to 8-membered (preferably 5- or 6-membered) cyclic amino, such as1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, morpholino, 1-piperazinyland 1-piperazinyl optionally having, at the 4-position, lower alkylgroup (e.g., C₁₋₆ alkyl group, such as methyl, ethyl, propyl, isopropyl,butyl, t-butyl, pentyl, hexyl etc., and the like), aralkyl group (e.g.,C₇₋₁₀ aralkyl group, such as benzyl, phenethyl etc., and the like), arylgroup (e.g., C₆₋₁₀ aryl group, such as phenyl, 1-naphthyl, 2-naphthyletc., and the like), and the like.

Examples of the “carbamoyl group optionally having a substituent orsubstituents” include unsubstituted carbamoyl, N-monosubstitutedcarbamoyl group and N,N-disubstituted carbamoyl group.

The “N-monosubstituted carbamoyl group” is a carbamoyl group having onesubstituent on the nitrogen atom.

Examples of the substituent include lower alkyl group (e.g., C₁₋₆ alkylgroup, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, pentyl, hexyl etc., and the like), cycloalkyl group (e.g., C₃₋₆cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl etc., and the like), aryl group (e.g., C₆₋₁₀ aryl group, suchas phenyl, 1-naphthyl, 2-naphthyl etc., and the like), aralkyl group(e.g., C₇₋₁₀ aralkyl group, such as benzyl, phenethyl etc., preferablyphenyl-C₁₋₄ alkyl group etc.), heterocyclic group (e.g., thoseexemplified as the “heterocyclic group” as a substituent of “hydrocarbongroup optionally having a substituent or substituents” represented byR^(c3) and the like). The lower alkyl group, cycloalkyl group, arylgroup, aralkyl group and heterocyclic group may have substituents, whichsubstituents are, for example, hydroxy group, amino group optionallyhaving a substituent or substituents [which amino group optionallyhaving 1 or 2 from lower alkyl group (e.g., C₁₋₆ alkyl group such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl,hexyl etc., and the like), acyl group (e.g., C₁₋₆ alkanoyl such asformyl, acetyl, propionyl, pivaloyl etc., benzoyl, etc.), and the likeas substituents], halogen atom (e.g., fluorine, chlorine, bromine,iodine etc.), nitro group, cyano group, lower alkyl group optionallyhaving 1 to 5 halogen atoms as substituents (e.g., fluorine, chlorine,bromine, iodine etc.) lower alkoxy group optionally having 1 to 5halogen atoms as substituents (e.g., fluorine, chlorine, bromine, iodineetc.), and the like. Examples of the lower alkyl group include C₁₋₆alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl etc., and the like,particularly preferably methyl, ethyl and the like. Examples of thelower alkoxy group include C₁₋₆ alkoxy group, such as methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxyetc., and the like, particularly preferably methoxy, ethoxy and thelike. One, two or three of these (preferably 1 or 2) are the same ordifferent and may be present.

The “N,N-disubstituted carbamoyl group” is a carbamoyl group having 2substituents on a nitrogen atom. Examples of one of the substituents arethose similar to the substituents of the aforementioned“N-monosubstituted carbamoyl group” and examples of the other includelower alkyl group (e.g., C₁₋₆ alkyl group, such as methyl, ethyl,propyl, isopropyl, butyl, t-butyl, pentyl, hexyl etc., and the like),C₃₋₆ cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl etc.), C₇₋₁₀ aralkyl group (e.g., benzyl, phenethyl etc.,preferably phenyl-C₁₋₄ alkyl group etc.) and the like. Two substituentsmay form a cyclic amino group together with a nitrogen atom. In thiscase, examples of the cyclic aminocarbamoyl group include 3 to8-membered (preferably 5- or 6-membered) cyclic amino-carbomoyl such as1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl,morpholinocarbonyl, 1-piperazinylcarbonyl and 1-piperazinylcarbonyloptionally having, at the 4-position, lower alkyl group (e.g., C₁₋₆alkyl group, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl,pentyl, hexyl etc., and the like), aralkyl group (e.g., C₇₋₁₀ aralkylgroup, such as benzyl, phenethyl etc., and the like), aryl group (e.g.,C₆₋₁₀ aryl group, such as phenyl, 1-naphthyl, 2-naphthyl etc., and thelike), and the like.

Examples of the substituent of the “thiocarbamoyl group optionallyhaving a substituent or substituents” are similar to those exemplifiedfor the substituent of the aforementioned “carbamoyl group optionallyhaving a substituent or substituents”.

Examples of the “sulfamoyl group optionally having a substituent orsubstituents” include unsubstituted sulfamoyl, N-monosubstitutedsulfamoyl group and N,N-disubstituted sulfamoyl group.

The “N-monosubstituted sulfamoyl group” means sulfamoyl group having onesubstituent on a nitrogen atom. Examples of the substituent are thosesimilar to the substituent of the “N-monosubstituted carbamoyl group”.The “N,N-disubstituted sulfamoyl group” means sulfamoyl group having 2substituents on a nitrogen atom. Examples of the substituent are thosesimilar to the substituent of the “N,N-disubstituted carbamoyl group”.

Examples of the “optionally esterified carboxyl group” include, besidesfree carboxyl group, lower alkoxy carbonyl group, aryloxycarbonyl group,aralkyloxycarbonyl group and the like.

Examples of the “lower alkoxy carbonyl group” include C₁₋₆alkoxy-carbonyl group, such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl,isopentyloxycarbonyl, neopentyloxycarbonyl etc., and the like. Of these,C₁₋₃ alkoxy-carbonyl group, such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl etc., and the like are preferable.

Examples of the “aryloxycarbonyl group” preferably include C₇₋₁₂aryloxy-carbonyl group, such as phenoxycarbonyl, 1-naphthoxycarbonyl,2-naphthoxycarbonyl etc., and the like.

Examples of the “aralkyloxycarbonyl group” preferably include C₇₋₁₀aralkyloxy-carbonyl group (preferably C₆₋₁₀ aryl-C₁₋₄ alkoxy-carbonyletc.) such as benzyloxycarbonyl, phenethyloxycarbonyl etc., and thelike.

The “aryloxycarbonyl group” and “aralkyloxycarbonyl group” may havesubstituents. Examples of the substituent are similar in the kind andthe number to those exemplified for the substituent of aryl group andaralkyl group as the substituents of the aforementionedN-monosubstituted carbamoyl group.

The “acyl group derived from carboxylic acid” as the substituent isexemplified by one in which a hydrogen atom or the single substituentthat the aforementioned “N-monosubstituted carbamoyl group” has on anitrogen atom is bonded to carbonyl, and the like. Preferably, C₁₋₆alkanoyl such as formyl, acetyl, propionyl, pivaloyl etc. and acyl suchas venzoyl etc., and the like.

The alkyl of the “alkyl sulfinyl group optionally having a substituentor substituents” and “alkyl sulfonyl group optionally having asubstituent or substituents” as the substituent may be, for example,lower alkyl group such as C₁₋₆ alkyl group (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl etc.), and the like.

The aryl of the “arylsulfinyl group optionally having a substituent orsubstituents” and “arylsulfonyl group optionally having a substituent orsubstituents” as the substituent may be, for example, C₆₋₁₄ aryl group,such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl etc.,and the like.

The substituent of these alkyl and aryl may be, for example, loweralkoxy group (e.g., C₁₋₆ alkoxy group, such as methoxy, ethoxy, propoxyetc., and the like), halogen atom (e.g., fluorine, chlorine, bromine,iodine etc.), lower alkyl group (e.g., C₁₋₆ alkyl group, such as methyl,ethyl, propyl etc., and the like), amino group, hydroxy group, cyanogroup, amidino group and the like, wherein one or two of these optionalsubstituents may be present at a substitutable position.

The hydrocarbon group optionally having a substituent or substituentsrepresented by R^(c4) is exemplified by those shown with regard tohydrocarbon group optionally having a substituent or substituentsrepresented by R^(c3), and the heterocyclic group optionally having asubstituent or substituents represented by R^(c4) is exemplified bythose shown with regard to the heterocyclic group optionally having asubstituent or substituents represented by R^(c3).

The divalent chain hydrocarbon group of the divalent chain hydrocarbongroup optionally having a substituent or substituents other than oxogroup, represented by E^(c), is exemplified by C₁₋₆ alkylene, such asmethylene, ethylene etc., C₂₋₆ alkenylene, such as ethenylene etc., C₂₋₆alkynylene, such as ethynylene etc., and the like. Preferred is C₁₋₅alkylene and more preferred is trimethylene.

The substituent of the divalent hydrocarbon group may be any as long asit is not an oxo group. Examples thereof include alkyl group optionallyhaving a substituent or substituents, an aryl group optionally having asubstituent or substituents, cycloalkyl group or cycloalkenyl groupoptionally having a substituent or substituents, optionally esterifiedcarboxyl group, carbamoyl group or thiocarbamoyl group optionally havinga substituent or substituents, amino group optionally having asubstituent or substituents, hydroxy group optionally having asubstituent or substituents, thiol (mercapto) group optionally having asubstituent or substituents, acyl group derived from carboxylic acid,alkyl sulfonyl group optionally having a substituent or substituents,arylsulfonyl group optionally having a substituent or substituents,halogen (e.g., fluorine, chlorine, bromine etc.), nitro, cyano and thelike. The number of the substituents may be 1 to 3. The alkyl groupoptionally having a substituent or substituents, the aryl groupoptionally having a substituent or substituents, the cycloalkyl group orcycloalkenyl group optionally having a substituent or substituents, theoptionally esterified carboxyl group, the carbamoyl group orthiocarbamoyl group optionally having a substituent or substituents, theamino group optionally having a substituent or substituents, the hydroxygroup optionally having a substituent or substituents, the thiol(mercapto) group optionally having a substituent or substituents, theacyl group derived from carboxylic acid, the alkyl sulfonyl groupoptionally having a substituent or substituents, the arylsulfonyl groupoptionally having a substituent or substituents are those similar to thesubstituent of the heterocyclic group optionally having a substituent orsubstituents represented by the aforementioned R^(c3).

Examples of the substituent of the methine group optionally having asubstituent or substituents represented by J^(c) are those similar tothe substituent of the heterocyclic group optionally having asubstituent or substituents represented by the aforementioned R^(c3).

The divalent chain C₁₋₃ hydrocarbon group of the divalent chain C₁₋₃hydrocarbon group optionally having a substituent or substituents,represented by Q^(c) and R^(c), is exemplified by one having 1 to 3carbon atoms from the divalent chain hydrocarbon group of the divalentchain hydrocarbon group optionally having a substituent or substituentsother than oxo group, represented by E^(c).

The substituent of the divalent chain C₁₋₃ hydrocarbon group optionallyhaving a substituent or substituents, represented by Q^(c) and R^(c), isexemplified by those exemplified as the substituent of the divalentchain hydrocarbon group optionally having a substituent or substituentsother than oxo group, represented by E^(c). The salt of the carboxylgroup or sulfonic acid group, as represented by R^(c5), is exemplifiedby salts with alkali metal, such as sodium, potassium, lithium etc.,salts with alkaline earth metal, such as calcium, magnesium, strontiumetc., ammonium salt and the like.

Among the compounds represented by the formula (III) or salts thereof(hereinafter referred to as Compound (III)), the following compounds arepreferable.

-   -   (III-1) The compound wherein R^(c1) is a C₁₋₆ alkyl group or a        C₃₋₈ cycloalkyl group; R^(c2) is a C₂₋₆ alkyl group or a C₃₋₈        cycloalkyl group, or R^(c1) and R^(c2) in combination form,        together with an adjacent nitrogen atom, a ring optionally        having a substituent or substituents; R^(c3) is a C₁₋₆ alkyl        group optionally having a substituent or substituents, a C₃₋₈        cycloalkyl group optionally having a substituent or        substituents, an aryl group optionally having a substituent or        substituents or a heterocyclic group optionally having a        substituent or substituents; R^(c4) is a hydrogen atom, alkyl        group optionally having a substituent or substituents, a C₃₋₈        cycloalkyl group optionally having a substituent or        substituents, an aryl group optionally having a substituent or        substituents or a heterocyclic group optionally having a        substituent or substituents; E^(c) is a C₂₋₅ alkylene group        optionally having a substituent or substituents other than oxo        group; G^(c) is CO or SO₂; J^(c) is a nitrogen atom or a methine        group optionally having a substituent or substituents; and Q^(c)        and R^(c) are each a bond or a C₁₋₃ alkylene group optionally        having a substituent or substituents.    -   (III-2) The compound wherein R^(c1) and R^(c2) in combination        form, together with an adjacent nitrogen atom, a ring optionally        having a substituent or substituents.    -   (III-3) The compound as shown in the above (III-2), wherein the        ring optionally having a substituent or substituents is a        1-piperidinyl group or a 1-piperazinyl group each optionally        having a substituent or substituents.    -   (III-4) The compound as shown in the above (III-3), wherein the        substituent of the 1-piperidinyl group or 1-piperazinyl group        is (1) phenyl-C₁₋₄ alkyl optionally having halogen on a benzene        ring, (2) diphenylmethyl optionally having hydroxy, (3) benzoyl        optionally having halogen on a benzene ring, (4)        2-phenylethen-1-yl, (5) phenyl optionally having halogen, (6)        hydroxy, (7) phenoxy or (8) benzyloxy.    -   (III-5) The compound as shown in the above (III-2), wherein the        ring optionally having a substituent or substituents is a        1-piperidinyl group optionally having a substituent or        substituents.    -   (III-6) The compound as shown in the above (III-5), wherein the        substituent of the 1-piperidinyl group is a benzyl group        optionally having halogen on a benzene ring.    -   (III-7) The compound wherein R^(c3) is (1) a C₁₋₆ alkyl        group, (2) a C₃₋₈ cycloalkyl group, (3) a benzyl group        optionally having a hydroxy group, (4) a naphthylmethyl        group, (5) a phenyl group optionally having, as a        substituent, (a) C₁₋₄ alkyl optionally having halogen, (b) C₁₋₄        alkoxy optionally having halogen, (c) phenyl, (d) cyano, (e)        benzyloxy or (f) a halogen atom, (6) a naphthyl group, (7) an        indanyl group or (8) a tetrahydronaphthyl group.    -   (III-8) The compound wherein R^(c3) is a phenyl group optionally        having, as a substituent, C₁₋₄ alkyl or halogen.    -   (III-9) The compound wherein E^(c) is C₂₋₆ polymethylene        optionally having hydroxy.    -   (III-10) The compound wherein R^(c4) is (1) a hydrogen atom, (2)        C₁₋₆ alkyl optionally having (a) halogen, (b) pyridyl, (c)        morpholino, (d) furyl, (e) ethynyl or (f) C₃₋₈ cycloalkyl, (3)        phenyl-C₁₋₄ alkyl optionally having (a) halogen, (b) C₁₋₄        alkyl, (c) halogeno-C₁₋₄ alkyl or (d) C₁₋₄ alkoxy on a benzene        ring, or (4) C₃₋₈ cycloalkyl.    -   (III-11) The compound wherein R^(c4) is (a) C₁₋₄ alkyl group        optionally having, as a substituent, halogen or furyl or (b) a        benzyl group optionally having halogen on a benzene ring.    -   (III-12) The compound wherein —N(R^(c1))R^(c2) is a        1-piperidinyl group optionally having a substituent or        substituents, E^(c) is a trimethylene group, R^(c3) is a phenyl        group optionally having a substituent or substituents, G^(c) is        CO, J^(c) is CH, and Q^(c) and R^(c) are each a methylene group.        In the above formulas, examples of the C₁₋₆ alkyl group shown by        R^(da) in groups —NR^(da)—SO₂— and —NR^(da)—CO—, which are        represented by B^(d) include e.g. methyl, ethyl, propyl,        isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, etc.,        examples of the C₂₋₆ alkenyl group include e.g. vinyl, allyl,        1-propeny, isopropeny, 2-butenyl, 3-butenyl, 2-hexenyl, etc.,        and examples of the C₃₋₈ cycloalkyl group include e.g.        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl,        etc.

Examples of the halogen atom represented by R^(d1) include e.g.fluorine, chlorine, bromine, iodine, etc., examples of the C₁₋₆ alkylgroup include e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, pentyl, hexyl, etc., examples of the C₂₋₄ alkenyl group includee.g. vinyl, 1-propeny, 2-propeny, isopropeny, butenyl, isobutenyl, etc.,example of C₁₋₄ alkanoyl group include e.g. formyl, acetyl, propionyl,butyryl, etc., and example of C₁₋₄ alkoxy group include e.g. methoxy,ethoxy, propoxy, etc.

Examples of halogen represented by R^(d2) include e.g. fluorine,chlorine, bromine, iodine, etc.

Examples of the C₁₋₆ alkyl in the “C₁₋₆ alkyl which may be substitutedby a halogen or C₁₋₄ alkoxy” represented by R^(d2) include e.g. methyl,ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, etc.,examples of the halogen as the substituent includes e.g. fluorine,chlorine, bromine, iodine, etc., and examples of C₁₋₄ alkoxy as thesubstituent include e.g. methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.

Examples of the C₁₋₄ alkoxy group in the C₁₋₄ alkoxy which may besubstituted by a halogen or C₁₋₄ alkoxy” represented by R^(d2) includee.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,sec-butoxy, tert-butoxy, etc., examples of the halogen as thesubstituent includes e.g. fluorine, chlorine, bromine, iodine, etc., andexamples of C₁₋₄ alkoxy as the substituent include e.g. methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy,etc.

Examples of C₁₋₄ alkanoylamino represented by R^(d2) include e.g.formylamino, acetylamino, propionylamino, butyrylamino, etc.

In the groups SO₂NR^(db)R^(dc), CONR^(db)R^(dc) and NR^(db)R^(dc) eachof which is represented by R^(d2), examples of the “C₁₋₆ alkyl groupwhich may be substituted by a halogen or C₁₋₄ alkoxy” represented byR^(db) and R^(dc) include those mentioned for the “C₁₋₆ alkyl which maybe substituted by a halogen or C₁₋₄ alkoxy” represented by R^(d2);examples of the “C₃₋₈ cycloalkyl group which may be substituted by ahalogen or C₁₋₄ alkoxy” include e.g. cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclooctyl, etc.; the halogen which is thesubstituent include e.g. fluorine, chlorine, bromine, iodine, etc., andthe C₁₋₄ alkoxy which is the substituent include e.g. methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy,etc.

In the groups SO₂NR^(db)R^(dc), CONR^(db)R^(dc) and NR^(db)R^(dc) eachof which is represented by R^(dc), examples of the cyclic amino groupwhich forms by combining R^(db) and R^(dc) together with the nitrogenatom include e.g. 1) 1-azetidinyl, 2) 1-pyrrolidinyl, 3) 1-piperidinyl,4) 4-morpholinyl, 5) 1-piperazinyl and 6) 1-piperazynyl which may besubstituted by a C₁₋₆ alkyl (e.g. methyl, ethyl, propyl, isopropyl,butyl, isobutyl, t-butyl, pentyl, hexyl, etc.), a C₇₋₁₀ aralkyl (e.g.benzyl, phenethyl, etc) or a C₆₋₁₀ aryl (e.g. phenyl, 1-naphthyl,2-naphthyl, etc.) at 4-position. In the group NR^(da)—SO₂R^(dd)represented by R^(d2), the definition of R^(da) is the same as that ofR^(da) in groups —NR^(da)—SO₂— and —NR^(da)—CO— each of whichrepresented by B^(d).

In the groups SO₂R^(dd) and —NR^(da)—SO₂R^(dd) represented by R^(d2),examples of the C₁₋₆alkyl group represented by R^(dd) include e.g.methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl,hexyl, etc. and examples of the C₃₋₈cycloalkyl group include, e.g.cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, etc.

In the formula (IV), (IIId) and (IVd), examples of the hydrocarbon groupin the hydrocarbon group which may be substituted represented by R^(d3)in the groups shown by the formulas (d1), (d2), (d3), (d4), (d5) and(d6) includes e.g. a C₁₋₆alkyl (e.g. methyl, ethyl, propyl, isopropyl,butyl, isobutyl, t-butyl, pentyl, hexyl, etc.), a C₂₋₆alkenyl (e.g.vinyl, allyl, 1-propeny, isopropeny, 2-butenyl, 3-butenyl, 2-hexenyl,etc.), a C₂₋₆alkynyl (e.g. ethynyl, 2-propynyl, 2-butynyl, 5-hexynyl,etc.), a C₃₋₈cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclooctyl, etc.), a C₆₋₁₀aryl (e.g. phenyl, naphthyl,etc.), etc.

Examples of the substituent of the hydrocarbon group include e.g. ahalogen (e.g. fluorine, chlorine, bromine, iodine, etc), aC₁₋₄alkoxy(e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec-butoxy, tert-butoxy, etc.), phenyl, a C₁₋₆alkyl (e.g.methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl, etc.), nitro, cyano, hydroxy, aC₁₋₄alkanoylamino (e.g. formylamino, acetylamino, propionylamino, etc.),carbamoyl, sulfamoyl, etc.

Among them, when the hydrocarbon group is a C₁₋₆alkyl, a C₂₋₆alkenyl orC₂₋₆alkynyl, preferable examples of the substituent include a halogen, aC₁₋₄alkoxy and phenyl; when the hydrocarbon group is a C₃₋₈cycloalkyl,preferable examples of the substituent include a halogen, a C₁₋₆alkyland a C₁₋₄alkoxy; when the hydrocarbon group is a C₆₋₁₀aryl, preferableexample include a halogen, a C₁₋₆alkyl, a C₁₋₄alkoxy, nitro, cyano,hydroxy, a C₁₋₄alkanoylamino, carbamoyl and sulfamoyl.

Examples of the C₁₋₄alkoxy in C₁₋₄alkoxy which may be substituentrepresented by R^(d3) include e.g. methoxy, ethoxy, propoxy, etc, andexample of the substituent in C₁₋₄alkoxy which may be substituentrepresented by R^(d3) include e.g. a halogen (e.g. fluorine, chlorine,bromine, iodine, etc.), phenyl, etc.

Examples of the amino group which may be substituted represented byR^(d3) include not only an unsubstituted amino group but also, e.g. aC₁₋₆alkylamino (e.g. methylamino, ethylamino, propylamino,isopropylamino, butylamino, isobutylamino, t-butylamino, pentylamino,hexylamino, etc.), a di(C₁₋₆alkyl)amino (e.g. dimethylamino,diethylamino, dipropylamino, dibutylamino, etc.), a C₁₋₄alkoxyamino(e.g. methoxyamino, ethoxyamino, n-propoxyamino, isopropoxyamino,n-butoxyamino, isobutoxyamino, sec-butoxyamino, tert-butoxyamino, etc.),etc.

Examples of the C₁₋₆ alkyl group represented by R^(d4) and R^(d5)include e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl,pentyl, hexyl, etc.

Examples of the C₁₋₆ alkyl group represented by R^(d6) include e.g.methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl,hexyl, etc. and examples of the C₂₋₆ alkenyl group include e.g. vinyl,allyl, 1-propeny, isopropeny, 2-butenyl, 3-butenyl, 2-hexenyl, etc.

Among the compounds of the formula (IV) or salts thereof (hereinafterreferred to as Compound (IV)), the following compounds are preferable.

-   -   (IV-1) a compound wherein R^(d3) is 1) C₁₋₆ alkyl group which        may be substituted by a halogen, a C₁₋₄ alkoxy or phenyl, 2) a        C₂₋₆alkenyl group, 3) a C₂₋₆alkynyl group, 4) a C₃₋₈cycloalkyl        group which may be substituted by a halogen, a C₁₋₆alkyl or a        C₁₋₄alkoxy, 5) a C₆₋₁₀aryl group which may be substituted by a        halogen, a C₁₋₆alkyl, a C₁₋₄alkoxy, nitro, cyano, hydroxy, a        C₁₋₄alkanoylamino, carbamoyl or sulfamoyl, 6) a C₁₋₄alkoxy group        which may be substituted by a halogen or phenyl, or 7) an amino        group which may be substituted by one or two groups selected        from the group consisting of a C₁₋₆alkyl and a C₁₋₄alkoxy;    -   (IV-2) a compound wherein R^(d3) is 1) C₁₋₆ alkyl group, 2) a        C₂₋₆alkenyl group, 3) a C₃₋₈cycloalkyl group, 4) a C₁₋₄alkoxy        group or 5) an amino group which may be substituted by a        C₁₋₆alkyl or a C₁₋₄alkoxy, X^(d) is —SO₂— or —CO—, nd is 1 or 2,        md is 0, 1 or 2, R^(d4) and R^(d5) are the same or different,        and each of which is a hydrogen atom or a methyl group, R^(d6)        is a hydroxy group, methyl group or a C₂₋₆alkenyl group, and rd        is 3.    -   (IV-3) a compound wherein A^(d) is a group of the formula:        wherein, R^(d3a) is a C₁₋₆alkyl group, X^(d1) is —SO₂— or —CO—,        nd1 is 1 or 2, R^(d6a) is a hydroxy group or a methyl group; rd        is 3, B^(d) is —CH₂—, each of pd and qd is 0, 1 or 2, R^(d1) is        a halogen atom, a methyl group, R^(d2) is a halogen, a        C₁₋₄alkoxy, nitro, a C₁₋₄alkanoylamino, SO₂NR^(db)R^(dc),        SO₂R^(dd), CONR^(db)R^(dc), NR^(db)R^(dc) or NR^(da)—SO₂R^(dd),        wherein R^(da) is a hydrogen atom, a C₁₋₆alkyl group, a        C₂₋₆alkenyl group or a C₃₋₈cycloalkyl group, R^(db) and R^(dc)        are the same or different, and each of which is a hydrogen atom,        a C₁₋₆alkyl group or a C₃₋₈cycloalkyl group, or R^(db) and        R^(dc) may combine each other together with the nitrogen atom to        form a cyclic amino group, R^(dd) is a C₁₋₆alkyl group or a        C₃₋₈cycloalkyl group.

“A 5- to 6-membered cyclic ring” of “a 5- to 6-membered cyclic ringgroup which may be substituted”, which is represented by R^(e1) in theabove-mentioned formula (eI), is exemplified by a group which is formedby removing one hydrogen atom from a 6-membered aromatic hydrocarbonsuch as benzene or the like, a 5- to 6-membered aliphatic hydrocarbonsuch as cyclopentane, cyclohexane, cyclopentene, cyclohexene,cyclopentadiene, cyclohexadiene or the like, a 5- to 6-membered aromaticheterocyclic ring, which contains 1 to 4 heteroatoms of 1 to 2 kindsselected from the nitrogen atom, the sulfur atom and the oxygen atom,such as furan, thiophene, pyrrole, imidazole, pyrazole, thiazole,oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine,pyrimidine, pyridazine, triazole or the like, a 5- to 6-membered,non-aromatic heterocyclic ring, which contains 1 to 4 heteroatoms of 1to 2 kinds selected from the nitrogen atom, the sulfur atom and theoxygen atom, such as tetrahydrofuran, tetrahydrothiophene, dithiolan,oxathiolan, pyrrolidine, pyrroline, imidazolidine, imidazoline,pyrazolidine, pyrazoline, piperidine, piperazine, oxazine, oxadiazine,thiazine, thiadiazine, morpholine, thiomorpholine, pyran,tetrahydropyran, tetrahydrothiopyran or the like, or the like, where asfor “a 5- to 6-membered cyclic ring” is preferably benzene, furan,thiophene, pyridine, cyclopentane, cyclohexane, pyrrolidine, piperidine,piperazine, morpholine, thiomorpholine, tetrahydropyran (preferably, a6-membered cyclic ring) or the like, particularly benzene.

Examples of “a substituent” which may be possessed by “a 5- to6-membered cyclic ring” of “a 5- to 6-membered cyclic ring group whichmay be substituted”, which is represented by R^(e1), to be used includea halogen atom, nitro, cyano, an alkyl which may be substituted, acycloalkyl which may be substituted, the hydroxyl group which may besubstituted, the thiol group which may be substituted (the sulfur atommay be oxidized to form a sulfinyl group which may be substituted or asulfonyl group which may be substituted), an amino group which may besubstituted, an acyl which may be substituted, the carboxyl group whichmay be esterified, an aromatic group which may be substituted and thelike.

A halogen as a substituent of R^(e1) is exemplified by fluorine,chlorine, bromine, iodine or the like, where fluorine and chlorine areparticularly preferable.

An alkyl for an alkyl which may be substituted as a substituent ofR^(e1) is exemplified by a straight-chain or branched alkyl having acarbon number of 1 to 10, for example, a C₁₋₁₀ alkyl such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl or thelike, preferably a lower (C₁₋₆) alkyl. A substituent in the alkyl whichmay be substituted is exemplified by a halogen (for example, fluorine,chlorine, bromine, iodine or the like), nitro, cyano, the hydroxylgroup, the thiol group which may be substituted (for example, thiol, aC₁₋₄ alkylthio or the like), an amino group which may be substituted(for example, amino, a mono-C₁₋₄ alkylamino, a di-C₁₋₄ alkylamino, a 5-to 6-membered cyclic ring amino such as tetrahydropyrrole, piperazine,piperidine, morpholine, thiomorpholine, pyrrole, imidazole or the like,or the like), the carboxyl group which may be esterified or amidated(for example, carboxyl, a C₁₋₄ alkoxycarbonyl, carbamoyl, a mono-C₁₋₄alkylcarbamoyl, a di-C₁₋₄ alkylcarbamoyl or the like), a C₁₋₄ alkoxylwhich may be halogenated (for example, methoxy, ethoxy, propoxy, butoxy,trifluoromethoxy, trifluoroethoxy or the like), a C₁₋₄ alkoxy-C₁₋₄alkoxyl which may be halogenated (for example, methoxymethoxy,methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy,trifluoroethoxyethoxy or the like), formyl, a C₂₋₄ alkanoyl (forexample, acetyl, propionyl or the like), a C₁₋₄ alkylsulfonyl (forexample, methanesulfonyl, ethanesulfonyl or the like) or the like, wherethe number of the substituents is preferably 1 to 3.

The cycloalkyl for a cycloalkyl which may be substituted as asubstituent of R^(e1) is exemplified by, for example, a C₃₋₇ cycloalkylsuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl orthe like. The substituent in the cycloalkyl which may be substituted isexemplified by a halogen (for example, fluorine, chlorine, bromine,iodine or the like), nitro, cyano, the hydroxyl group, the thiol groupwhich may be substituted (for example, thiol, a C₁₋₄ alkylthio or thelike), an amino group which may be substituted (for example, amino, amono-C₁₋₄ alkylamino, a di-C₁₋₄ alkylamino, a 5- to 6-membered cyclicring amino such as tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole, imidazole or the like, or thelike), the carboxyl group which may be esterified or amidated (forexample, carboxyl, a C₁₋₄ alkoxycarbonyl, carbamoyl, a mono-C₁₋₄alkylcarbamoyl, a di-C₁₋₄ alkylcarbamoyl or the like), a C₁₋₄ alkoxylwhich may be halogenated (for example, methoxy, ethoxy, propoxy, butoxy,trifluoromethoxy, trifluoroethoxy or the like), a C₁₋₄ alkoxy-C₁₋₄alkoxyl which may be halogenated (for example, methoxymethoxy,methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy,trifluoroethoxyethoxy or the like), formyl, a C₂₋₄ alkanoyl (forexample, acetyl, propionyl or the like), a C₁₋₄ alkylsulfonyl (forexample, methanesulfonyl, ethanesulfonyl or the like) or the like, wherethe number of the substituents is preferably 1 to 3.

The substituent for the hydroxyl group which may be substituted as asubstituent of R^(e1) is exemplified by a substituent such as (1) analkyl which may be substituted (for example, a C₁₋₁₀ alkyl such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl,decyl or the like, preferably a lower (C₁₋₆) alkyl, etc.);

-   (2) a cycloalkyl which may be substituted and may contain    heteroatoms (for example, a C₃₋₇ cycloalkyl such as cyclopropyl,    cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or the like; a    saturated, 5- to 6-membered heterocyclic ring group containing 1 to    2 heteroatoms such as tetrahydrofuranyl, tetrahydrothienyl,    pyrrolidinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholinyl,    thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl or the    like (preferably, tetrahydropyranyl or the like); or the like is    exemplified);-   (3) an alkenyl which may be substituted (for example, an alkenyl    which has the carbon number of 2 to 10 such as allyl, crotyl,    2-pentenyl, 3-hexenyl or the like, preferably a lower (C₂₋₆)    alkenyl, or the like is exemplified);-   (4) a cycloalkenyl which may be substituted (for example, an    cycloalkenyl which has the carbon number of 3 to 7 such as    2-cyclopentenyl, 2-cyclohexenyl 2-cyclopentenylmethyl,    2-cyclohexenylmethyl or the like, or the like is exemplified);-   (5) an aralkyl which may be substituted (for example, a phenyl-C₁₋₄    alkyl (for example, benzyl, phenethyl or the like) or the like is    exemplified);-   (6) formyl or an acyl which may be substituted (for example, an    alkanoyl which has the carbon number of 2 to 4 (for example, acetyl,    propionyl, butyryl, isobutyryl or the like), an alkylsulfonyl which    has the carbon number of 1 to 4 (for example, methanesulfonyl,    ethanesulfonyl or the like) or the like is exemplified); and-   (7) an aryl which may be substituted (for example, phenyl, naphthyl    or the like is exemplified),-   where examples of the substituents which may be possessed by (1) an    alkyl which may be substituted, (2) a cycloalkyl which may be    substituted, (3) an alkenyl which may be substituted, (4) a    cycloalkenyl which may be substituted, (5) an aralkyl which may be    substituted, (6) an acyl which may be substituted and (7) an aryl    which may be substituted include a halogen (for example, fluorine,    chlorine, bromine, iodine or the like), nitro, cyano, the hydroxyl    group, the thiol group which may be substituted (for example, thiol,    a C₁₋₄ alkylthio or the like), an amino group which may be    substituted (for example, amino, a mono-C₁₋₄ alkylamino, a di-C₁₋₄    alkylamino, a 5- to 6-membered cyclic ring amino such as    tetrahydropyrrole, piperazine, piperidine, morpholine,    thiomorpholine, pyrrole, imidazole or the like, or the like), the    carboxyl group which may be esterified or amidated (for example,    carboxyl, a C₁₋₄ alkoxycarbonyl, carbamoyl, a mono-C₁₋₄    alkylcarbamoyl, a di-C₁₋₄ alkylcarbamoyl or the like), a C₁₋₄ alkyl    which may be halogenated (for example, trifluoromethyl, methyl,    ethyl or the like), a C₁₋₆ alkoxyl which may be halogenated (for    example, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,    trifluoroethoxy or the like; preferably, a C₁₋₄ alkoxyl which may be    halogenated), formyl, a C₂₋₄ alkanoyl (for example, acetyl,    propionyl or the like), a C₁₋₄ alkylsulfonyl (for example,    methanesulfonyl, ethanesulfonyl or the like), a 5- to 6-membered,    aromatic heterocyclic ring which may be substituted [for example, an    aromatic heterocyclic ring, which contains 1 to 4 heteroatoms of 1    to 2 kinds selected from the nitrogen atom, the sulfur atom and the    oxygen atom, such as furan, thiophene, pyrrole, imidazole, pyrazole,    thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine,    pyrazine, pyrimidine, pyridazine, triazole or the like; the    substituent which may be possessed by the heteroaromatic ring is    exemplified by a halogen (for example, fluorine, chlorine, bromine,    iodine or the like), nitro, cyano, the hydroxyl group, the thiol    group, an amino group, the carboxyl group, a C₁₋₄ alkyl which may be    halogenated (for example, trifluoromethyl, methyl, ethyl or the    like), a C₁₋₄ alkoxyl which may be halogenated (for example,    methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy    or the like), formyl, a C₂₋₄ alkanoyl (for example, acetyl,    propionyl or the like), a C₁₋₄ alkylsulfonyl (for example,    methanesulfonyl, ethanesulfonyl or the like), where the number of    the substituents is preferably 1 to 3.], or the like, where the    number of the substituents is preferably 1 to 3.

The substituent for the thiol group which may be substituted as asubstituent of R^(e1) is exemplified by a substituent similar to “asubstituent for the hydroxyl group which may be substituted as asubstituent of R^(e1)”, among which preferable is

-   (1) an alkyl which may be substituted (for example, a C₁₋₁₀ alkyl    such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,    sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl,    octyl, nonyl, decyl or the like, preferably a lower (C₁₋₆) alkyl, or    the like is exemplified);-   (2) a cycloalkyl which may be substituted (for example, a C₃₋₇    cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    cycloheptyl or the like is exemplified);-   (3) an aralkyl which may be substituted (for example, a phenyl-C₁₋₄    alkyl (for example, benzyl, phenethyl or the like) or the like is    exemplified); and-   (4) an aryl which may be substituted (for example, phenyl, naphthyl    or the like is exemplified),-   where examples of the substituents which may be possessed by (1) an    alkyl which may be substituted, (2) a cycloalkyl which may be    substituted, (3) an aralkyl which may be substituted and (4) an aryl    which may be substituted, which are described above, include a    halogen (for example, fluorine, chlorine, bromine, iodine or the    like), nitro, cyano, the hydroxyl group, the thiol group which may    be substituted (for example, thiol, a C₁₋₄ alkylthio or the like),    an amino group which may be substituted (for example, amino, a    mono-C₁₋₄ alkylamino, a di-C₁₋₄ alkylamino, a 5- to 6-membered    cyclic ring amino such as tetrahydropyrrole, piperazine, piperidine,    morpholine, thiomorpholine, pyrrole, imidazole or the like, or the    like), the carboxyl group which may be esterified or amidated (for    example, carboxyl, a C₁₋₄ alkoxycarbonyl, carbamoyl, a mono-C₁₋₄    alkylcarbamoyl, a di-C₁₋₄ alkylcarbamoyl or the like), a C₁₋₄    alkoxyl which may be halogenated (for example, methoxy, ethoxy,    propoxy, butoxy, trifluoromethoxy, trifluoroethoxy or the like), a    C₁₋₄ alkoxy-C₁₋₄ alcoxy which may be halogenated (for example,    methoxymethoxy, methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy,    trifluoroethoxyethoxy or the like), formyl, a C₂₋₄ alkanoyl (for    example, acetyl, propionyl or the like), a C₁₋₄ alkylsulfonyl (for    example, methanesulfonyl, ethanesulfonyl or the like), where the    number of the substituents is preferably 1 to 3.

The substituent for the amino group which may be substituted as thesubstituent of R^(e1) is exemplified by an amino group which may have 1to 2 substituents similar to “a substituent for the hydroxyl group whichmay be substituted as a substituent of R^(e1)”, among which preferableis (1) an alkyl which may be substituted (for example, a C₁₋₁₀ alkylsuch as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl,decyl or the like, preferably a lower (C₁₋₆) alkyl, or the like isexemplified);

-   (2) a cycloalkyl which may be substituted (for example, a C₃₋₇    cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    cycloheptyl or the like);-   (3) an alkenyl which may be substituted (for example, an alkenyl    which has the carbon number of 2 to 10 such as allyl, crotyl,    2-pentenyl, 3-hexenyl or the like, preferably a lower (C₂₋₆)    alkenyl, or the like is exemplified);-   (4) a cycloalkenyl which may be substituted (for example, an    cycloalkenyl which has the carbon number of 3 to 7 such as    2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl,    2-cyclohexenylmethyl or the like, or the like is exemplified);-   (5) formyl, or an acyl which may be substituted (for example, an    alkanoyl which has the carbon number of 2 to 4 (for example, acetyl,    propionyl, butyryl, isobutyryl or the like), an alkylsulfonyl which    has the carbon number of 1 to 4 (for example, methanesulfonyl,    ethanesulfonyl or the like) or the like is exemplified); and-   (6) an aryl which may be substituted (for example, phenyl, naphthyl    or the like is exemplified),-   where examples of the substituents which may be possessed by (1) an    alkyl which may be substituted, (2) a cycloalkyl which may be    substituted, (3) an alkenyl which may be substituted, (4) a    cycloalkenyl which may be substituted, (5) an acyl which may be    substituted and (6) an aryl which may be substituted, which are    described above, include a halogen (for example, fluorine, chlorine,    bromine, iodine or the like), nitro, cyano, the hydroxyl group, the    thiol group which may be substituted (for example, thiol, a C₁₋₄    alkylthio or the like), an amino group which may be substituted (for    example, amino, a mono-C₁₋₄ alkylamino, a di-C₁₋₄ alkylamino, a 5-    to 6-membered cyclic ring amino such as tetrahydropyrrole,    piperazine, piperidine, morpholine, thiomorpholine, pyrrole,    imidazole or the like, or the like), the carboxyl group which may be    esterified or amidated (for example, carboxyl, a C₁₋₄    alkoxycarbonyl, carbamoyl, a mono-C₁₋₄ alkylcarbamoyl, a di-C₁₋₄    alkylcarbamoyl or the like), a C₁₋₄ alkoxy which may be halogenated    (for example, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,    trifluoroethoxy or the like), C₁₋₄ alkoxy-C₁₋₄ alkoxy which may be    halogenated (for example, methoxymethoxy, methoxyethoxy,    ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy or the    like) formyl, a C₂₋₄ alkanoyl (for example, acetyl, propionyl or the    like), a C₁₋₄ alkylsulfonyl (for example, methanesulfonyl,    ethanesulfonyl or the like), where the number of the substituents is    preferably 1 to 3.

In addition, as for the substituents for an amino group which may besubstituted as a substituent of R^(e1), the substituents for the aminogroup may bind together to form a cyclic ring amino group (for example,a cyclic ring amino group which is formed by removing one hydrogen fromthe nitrogen atom constituting the ring of a 5- to 6-membered cyclicring such as tetrahydropyrrole, piperazine, piperidine, morpholine,thiomorpholine, pyrrole, imidazole or the like, and has a bond on thenitrogen atom). The cyclic ring amino group may have substituents, andsuch substituents are exemplified by a halogen (for example, fluorine,chlorine, bromine, iodine or the like), nitro, cyano, a hydroxyl group,a thiol group which may be substituted (for example, thiol, a C₁₋₄alkylthio or the like), an amino group which may be substituted (forexample, amino, a mono-C₁₋₄ alkylamino, a di-C₁₋₄ alkylamino, a 5- to6-membered cyclic ring amino such as tetrahydropyrrole, piperazine,piperidine, morpholine, thiomorpholine, pyrrole, imidazole or the like,or the like), the carboxyl group which may be esterified or amidated(for example, carboxyl, a C₁₋₄ alkoxycarbonyl, carbamoyl, a mono-C₁₋₄alkylcarbamoyl, a di-C₁₋₄ alkylcarbamoyl or the like), a C₁₋₄ alkoxywhich may be halogenated (for example, methoxy, ethoxy, propoxy, butoxy,trifluoromethoxy, trifluoroethoxy or the like), a C₁₋₄ alkoxy-C₁₋₄alkoxy which may be halogenated (for example, methoxymethoxy,methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy,trifluoroethoxyethoxy or the like), formyl, a C₂₋₄ alkanoyl (forexample, acetyl, propionyl or the like), a C₁₋₄ alkylsulfonyl (forexample, methanesulfonyl, ethanesulfonyl or the like), where the numberof the substituents is preferably 1 to 3.

The acyl which may be substituted as a substituent of R^(e1) isexemplified by a group, wherein the carbonyl group or the sulfonyl groupis bonded with

-   (1) hydrogen,-   (2) an alkyl which may be substituted (for example, a C₁₋₁₀ alkyl    such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,    sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl,    octyl, nonyl, decyl or the like, preferably a lower (C₁₋₆) alkyl, or    the like is exemplified);-   (3) a cycloalkyl which may be substituted (for example, a C₃₋₇    cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    cycloheptyl or the like);-   (4) an alkenyl which may be substituted (for example, an alkenyl    which has the carbon number of 2 to 10 such as allyl, crotyl,    2-pentenyl, 3-hexenyl or the like, preferably a lower (C₂₋₆)    alkenyl, or the like is exemplified);-   (5) a cycloalkenyl which may be substituted (for example, an    cycloalkenyl which has the carbon number of 3 to 7 such as    2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl,    2-cyclohexenylmethyl or the like, or the like is exemplified); or-   (6) a 5- to 6-membered, monocyclic ring aromatic group which may be    substituted (for example, phenyl, pyridyl or the like is    exemplified), which is bonded with a carbonyl group or a sulfonyl    group, (for example, acetyl, propionyl, butyryl, isobutyryl,    valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl,    cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl,    cycloheptanecarbonyl, crotonyl, 2-cyclohexenecarbonyl, benzoyl,    nicotinoyl, methanesulfonyl, ethanesulfonyl or the like), where    examples of the substituents which may be possessed by (2) the alkyl    which may be substituted, (3) the cycloalkyl which may be    substituted, (4) the alkenyl which may be substituted, (5) the    cycloalkenyl which may be substituted and (6) the 5- to 6-membered,    monocyclic ring aromatic group which may be substituted, which are    described above, include a halogen (for example, fluorine, chlorine,    bromine, iodine or the like), nitro, cyano, a hydroxyl group, a    thiol group which may be substituted (for example, thiol, a C₁₋₄    alkylthio or the like), an amino group which may be substituted (for    example, amino, a mono-C₁₋₄ alkylamino, a di-C₁₋₄ alkylamino, a 5-    to 6-membered cyclic ring amino such as tetrahydropyrrole,    piperazine, piperidine, morpholine, thiomorpholine, pyrrole,    imidazole or the like, or the like), a carboxyl group which may be    esterified or amidated (for example, carboxyl, a C₁₋₄    alkoxycarbonyl, carbamoyl, a mono-C₁₋₄ alkylcarbamoyl, a di-C₁₋₄    alkylcarbamoyl or the like), a C₁₋₄ alkoxy which may be halogenated    (for example, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,    trifluoroethoxy or the like), a C₁₋₄ alkoxy-C₁₋₄ alkoxy which may be    halogenated (for example, methoxymethoxy, methoxyethoxy,    ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy or the    like), formyl, a C₂₋₄ alkanoyl (for example, acetyl, propionyl or    the like), a C₁₋₄ alkylsulfonyl (for example, methanesulfonyl,    ethanesulfonyl or the like), where the number of the substituents is    preferably 1 to 3.

The carboxyl group which may be esterified as a substituent of R^(e1) isexemplified by a group, wherein the carbonyloxy group is bonded with

-   (1) hydrogen,-   (2) an alkyl which may be substituted (for example, a C₁₋₁₀ alkyl    such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,    sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl,    octyl, nonyl, decyl or the like, preferably a lower (C₁₋₆) alkyl, or    the like is exemplified);-   (3) a cycloalkyl which may be substituted and may contain    heteroatoms (for example, a C₃₋₇ cycloalkyl such as cyclopropyl,    cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or the like);-   (4) an alkenyl which may be substituted (for example, an alkenyl    which has the carbon number of 2 to 10 such as allyl, crotyl,    2-pentenyl, 3-hexenyl or the like, preferably a lower (C₂₋₆)    alkenyl, or the like is exemplified);-   (5) a cycloalkenyl which may be substituted (for example, an    cycloalkenyl which has the carbon number of 3 to 7 such as    2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl,    2-cyclohexenylmethyl or the like, or the like is exemplified); or-   (6) an aryl which may be substituted (for example, phenyl, naphthyl    or the like is exemplified), preferably carboxyl, a lower (C₁₋₆)    alkoxycarbonyl and an aryloxycarbonyl (for example, methoxycarbonyl,    ethoxycarbonyl, propoxycarbonyl, phenoxycarbonyl, naphthoxycarbonyl    or the like), where examples of the substituents which may be    possessed by (2) an alkyl which may be substituted, (3) a cycloalkyl    which may be substituted, (4) an alkenyl which may be    substituted, (5) a cycloalkenyl which may be substituted and (6) an    aryl which may be substituted, which are described above, include a    halogen (for example, fluorine, chlorine, bromine, iodine or the    like), nitro, cyano, a hydroxyl group, a thiol group which may be    substituted (for example, thiol, a C₁₋₄ alkylthio or the like), an    amino group which may be substituted (for example, amino, a    mono-C₁₋₄ alkylamino, a di-C₁₋₄ alkylamino, a 5- to 6-membered    cyclic ring amino such as tetrahydropyrrole, piperazine, piperidine,    morpholine, thiomorpholine, pyrrole, imidazole or the like, or the    like), the carboxyl group which may be esterified or amidated (for    example, carboxyl, a C₁₋₄ alkoxycarbonyl, carbamoyl, a mono-C₁₋₄    alkylcarbamoyl, a di-C₁₋₄ alkylcarbamoyl or the like), a C₁₋₄ alkoxy    which may be halogenated (for example, methoxy, ethoxy, propoxy,    butoxy, trifluoromethoxy, trifluoroethoxy or the like), a C₁₋₄    alkoxy-C₁₋₄ alkoxy which may be halogenated (for example,    methoxymethoxy, methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy,    trifluoroethoxyethoxy or the like), formyl, a C₂₋₄ alkanoyl (for    example, acetyl, propionyl or the like), a C₁₋₄ alkylsulfonyl (for    example, methanesulfonyl, ethanesulfonyl or the like), where the    number of the substituents is preferably 1 to 3.

The aromatic group for an aromatic group which may be substituted as asubstituent of R^(e1) is exemplified by a 5- to 6-membered, same elementor heterocyclic ring, aromatic group such as phenyl, pyridyl, furyl,thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl,isothiazolyl, isooxazolyl, tetrazolyl, pirazinyl, pyrimidinyl,pyridazinyl, triazolyl or the like, a condensed, heterocyclic ringaromatic group such as benzofuran, indole, benzothiophene, benzoxazole,benzthiazole, indazole, benzimidazole, quinoline, isoquinoline,quinoxaline, phthalazine, quinazoline, cinnoline or the like, or thelike. Examples of the substituents for these aromatic groups include ahalogen (for example, fluorine, chlorine, bromine, iodine or the like),nitro, cyano, the hydroxyl group, the thiol group which may besubstituted (for example, thiol, a C₁₋₄ alkylthio or the like), an aminogroup which may be substituted (for example, amino, a mono-C₁₋₄alkylamino, a di-C₁₋₄ alkylamino, a 5- to 6-membered cyclic ring aminosuch as tetrahydropyrrole, piperazine, piperidine, morpholine,thiomorpholine, pyrrole, imidazole or the like, or the like), thecarboxyl group which may be esterified or amidated (for example,carboxyl, a C₁₋₄ alkoxycarbonyl, carbamoyl, a mono-C₁₋₄ alkylcarbamoyl,a di-C₁₋₄ alkylcarbamoyl or the like), a C₁₋₄ alkyl which may behalogenated (for example, trifluoromethyl, methyl, ethyl or the like), aC₁₋₄ alkoxy which may be halogenated (for example, methoxy, ethoxy,propoxy, butoxy, trifluoromethoxy, trifluoroethoxy or the like), formyl,a C₂₋₄ alkanoyl (for example, acetyl, propionyl or the like), a C₁₋₄alkylsulfonyl (for example, methanesulfonyl, ethanesulfonyl or thelike), where the number of the substituents is preferably 1 to 3.

One to four (preferably one or two) of these substituents of R^(e1) maybe the same or different and present at any position. Also, in the casewhere “a 5- to 6-membered cyclic ring” of “a 5- to 6-membered cyclicring which may be substituted”, which is represented by R^(e1), has 2 ormore substituents, 2 substituents of them may be bonded together toform, for example, a lower (C₁₋₆) alkylene (for example, trimethylene,tetramethylene or the like), a lower (C₁₋₆) alkyleneoxy (for example,—CH₂—O—CH₂—, —O—CH₂—CH₂—, —O—CH₂—CH₂—CH₂—, —O—CH₂—CH₂—CH₂—CH₂—,—O—C(CH₃) (CH₃)—CH₂—CH₂— or the like), a lower (C₁₋₆) alkylenethio (forexample, —CH₂—S—CH₂—, —S—CH₂—CH₂—, —S—CH₂—CH₂—CH₂—, —S—CH₂—CH₂—CH₂—CH₂—,—S—C(CH₃) (CH₃)—CH₂—CH₂— or the like), a lower (C₁₋₆) alkylenedioxy (forexample, —O—CH₂—O—, —O—CH₂—CH₂—O—, —O—CH₂—CH₂—CH₂—O— or the like), alower (C₁₋₆) alkylenedithio (for example, —S—CH₂—S—, —S—CH₂—CH₂—S—,—S—CH₂—CH₂—CH₂—S— or the like), an oxy-lower (C₁₋₆) alkylenamino (forexample, —O—CH₂—NH—, —O—CH₂—CH₂—NH— or the like), an oxy-lower (C₁₋₆)alkylenethio (for example, —O—CH₂—S—, —O—CH₂—CH₂—S— or the like), alower (C₁₋₆) alkylenamino (for example, —NH—CH₂—CH₂—, —NH—CH₂—CH₂—CH₂—or the like), a lower (C₁₋₆) alkylenediamino (for example, —NH—CH₂—NH—,—NH—CH₂—CH₂—NH— or the like), a thia-lower (C₁₋₆) alkylenamino (forexample, —S—CH₂—NH—, —S—CH₂—CH₂—NH— or the like), a lower (C₂₋₆)alkenylene (for example, —CH₂—CH═CH—, —CH₂—CH₂—CH═CH—,—CH₂—CH═CH—CH₂—CH₂— or the like), a lower (C₄₋₆) alkadienylene (forexample, —CH═CH—CH═CH— or the like) or the like.

Furthermore, the bivalent group which is formed by binding each other 2substituents of R^(e1) may have 1 to 3 substituents similar to “thesubstituent” which may be possessed by “a 5- to 6-membered cyclic ring”of “a 5- to 6-membered cyclic ring which may be substituted”, which isrepresented by R^(e1), (a halogen atom, nitro, cyano, an alkyl which maybe substituted, a cycloalkyl which may be substituted, the hydroxylgroup which may be substituted, the thiol group which may be substituted(the sulfur atom may be oxidized to form a sulfinyl group which may besubstituted or a sulfonyl group which may be substituted), an aminogroup which may be substituted, an acyl which may be substituted, thecarboxyl group which may be esterified or amidated, an aromatic groupwhich may be substituted and the like).

“The substituent” which may be possessed by “a 5- to 6-membered cyclicring” of “a 5- to 6-membered cyclic ring which may be substituted”,which is represented by R^(e1), is exemplified particularly by a lower(C₁₋₄) alkyl which may be halogenated or alkoxylated with a lower (C₁₋₄)alkyl (for example, methyl, ethyl, t-butyl, trifluoromethyl,methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, methoxyethyl,ethoxyethyl, propoxyethyl, butoxyethyl, or the like), a lower (C₁₋₄)alkoxyl which may be halogenated or alkoxylated with a lower (C₁₋₄)alkyl (for example, methoxy, ethoxy, propoxy, butoxy, t-butoxy,trifluoromethoxy, methoxymethoxy, ethoxymethoxy, propoxymethoxy,butoxymethoxy, methoxyethoxy, ethoxymethoxy, propoxyethoxy,butoxyethoxy, methoxypropoxy, ethoxypropoxy, propoxypropoxy,butoxypropoxy or the like), a halogen (for example, fluorine, chlorineor the like), nitro, cyano, an amino group which may be substituted with1 to 2 of a lower (C₁₋₄) alkyl, formyl or a lower (C₂₋₄) alkanoyl (forexample, amino, methylamino, dimethylamino, formylamino, acetylamino orthe like), a 5- to 6-membered cyclic ring amino group (for example,1-pyrrolidinyl, 1-piperazinyl, 1-piperidinyl, 4-morpholino,4-thiomorpholino, 1-imidazolyl, 4-tetrahydropyranyl or the like) or thelike.

“A bivalent group, in which the number of atoms constituting thestraight-chain portion is 1 to 4”, represented by X^(e1) and X^(e2), isexemplified by, for example, —(CH₂)_(ea′)— [ea′ represents an integer of1 to 4 (preferably, an integer of 1 to 2)], —(CH₂)_(eb′)——X^(e3)— [eb′represents an integer of 0 to 3 (preferably, an integer of 0 to 1) andX^(e3) represents an imino group which may be substituted (for example,an imino group which may be substituted with a lower (C₁₋₆) lower alkyl,a lower (C₃₋₇) cycloalkyl, formyl, a lower (C₂₋₇) lower alkanoyl, alower (C₁₋₆) lower alkoxycarbonyl or the like), the carbonyl group, theoxygen atom, the sulfur atom which may be oxidized by the oxygen atom(for example, —S(O)_(em)— (em represents an integer of 0 to 2) or thelike)], —CH═CH—, —C≡C—, —CO—NH—, —SO₂—NH— or the like. Although thesegroups may be bonded with W^(e) through either of the left or rightbond, it is preferable to be bonded with W^(e) through the right hand inthe case of X^(e1), whereas it is preferable to be bonded with W^(e)through the left hand in the case of X^(e2).

As for X^(e1), a bond, —(CH₂)_(eb′)—O— [eb′ is an integer of 0, 1 or 2(preferably, an integer of 0 to 1), —C≡C— or the like is preferable, anda bond is more preferable.

As for X^(e2), —(CH₂)_(ea″)— [ea″ is an integer of 1 to 2],—(CH₂)_(eb″)—X^(e3)— [eb″ is an integer of 0 to 1 and X^(e3) is an iminogroup which may be substituted, the carbonyl group, the oxygen atom, thesulfur atom which may be oxidized by the oxygen atom], —CH═CH—, —CO—NH—,—SO₂—NH— or the like is preferable, and —CO—NH— is more preferable.

In the above-mentioned formula (eI), a bivalent group which isrepresented by formula representd by W^(e)

(wherein each of ring A^(e) and ring B^(e) is a 5- to 7-membered cyclicring group which may be substituted, each of E_(e1) and E_(e4)represents the carbon atom which may be substituted or the nitrogen atomwhich may be substituted, each of E_(e2) and E_(e3) represents thecarbon atom which may be substituted or the nitrogen atom which may besubstituted, the sulfur atom which may be oxidized (for example,—S(O)_(em)— (em represents an integer of 0 to 2) or the like) or theoxygen atom and each of ea and eb represents to be a single bond or adouble bond) represents which the bonding with adjacent X^(e1) andX^(e2) is made in a mode which is shown respectively by

(wherein each of the symbols has the meaning defined above).

In the above-mentioned formula (eI), “a 5- to 7-membered cyclic ring” of“a 5- to 7-membered cyclic ring which may be substituted”, which isrepresented by A^(e), is exemplified by a 5- to 7-membered (preferably,5- to 6-membered, saturated or unsaturated alicyclic hydrocarbon such asa C₅₋₇ cycloalkane (for example, cyclopentane, cyclohexane, cycloheptaneor the like), a C₅₋₇ cycloalkene (for example, 1-cyclopentene,2-cyclopentene, 3-cyclopentene, 2-cyclohexene, 3-cyclohexene or thelike), a C₅₋₆ cycloalkadiene (for example, 2,4-cyclopentadiene,2,4-cyclohexadiene, 2,5-cyclohexadiene or the like); a 6-memberedaromatic hydrocarbon such as benzene; a 5- to 7-membered, aromaticheterocyclic ring, a saturated or unsaturated non-aromatic heterocyclicring (aliphatic heterocyclic ring) or the like, which contains at leastone (preferably, 1 to 4, more preferably 1 to 2) of heteroatoms of 1 to3 kinds (preferably, 1 to 2 kinds) selected from the oxygen atom, thesulfur atom and the nitrogen atom; or the like.

Herein, “an aromatic heterocyclic ring” is exemplified by a 5- to7-membered, aromatic monocyclic heterocyclic ring (for example, furan,thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole,imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole,1,3,4-oxadiazole, furazane, 1,2,3-thiadiazole, 1,2,4-thiadiazole,1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine,pyridazine, pyrimidine, pyrazine, triazine or the like) or the like, and“a non-aromatic heterocyclic ring” is exemplified by, for example, a 5-to 7-membered (preferably, 5- to 6-membered), saturated or unsaturatednon-aromatic heterocyclic ring (aliphatic heterocyclic ring) such aspyrrolidine, tetrahydrofuran, thiolan, piperidine, tetrahydropyran,morpholine, thiomorpholine, piperazine, pyran, oxepine, thiepin, azepineor the like, or a 5- to 6-membered, non-aromatic heterocyclic ring,where a part or all of the double bonds in the above-mentioned aromaticmonocyclic heterocyclic ring are saturated, or the like.

As for “a 5- to 7-membered cyclic ring” of “a 5- to 7-membered cyclicring which may be substituted”, which is represented by A^(e), a 5- to6-membered, aromatic ring is preferable, and further benzene, furan,thiophene, pyrrole, pyridine (preferably, 6-membered) or the like ispreferable, where benzene is particularly preferable.

“The substituent” which may be possessed by “a 5- to 7-membered cyclicring” of “a 5- to 7-membered cyclic ring which may be substituted”,which is represented by A^(e), is exemplified by a group similar to “thesubstituent” which may be possessed by “a 5- to 6-membered cyclic ring”of “a 5- to 6-membered cyclic ring which may be substituted”, which isrepresented by R^(e1). Also, 1 to 4 (preferably, 1 to 2) of thesubstituent for A^(e) may be present at any positions of the same ordifferent rings, and the substituent may be possessed at anysubstitutable position, whether it is any of the positions that arerepresentd by E_(e1) and E_(e2) or any of other positions.

In the above-mentioned formula (eI), “a 5- to 7-membered cyclic ring” of“a 5- to 7-membered cyclic ring which may be substituted”, which isrepresented by B, is exemplified by a 5- to 7-membered cyclic ring whichmay have substituents at optional, substitutable positions, which isrepresented by formula

or the like.

In the above-mentioned formula (eI), the bivalent group which isrepresented by Y^(e) is a bivalent group, with which ring B^(e) forms a5- to 7-membered cyclic ring which may be substituted, and isexemplified by a bivalent group such as, for example,

-   (1) —(CH₂)_(ea1)—O—(CH₂)_(ea2)— (each of ea1 and ea2 represents 0, 1    or 2 in the same or different manner. Hereupon, the sum of ea1 and    ea2 is 2 or less), —O—(CH═CH)—, —(CH═CH)—O—,-   (2) —(CH₂)_(eb1)—S(O)_(em)—(CH₂)_(eb2)— (em represents an integer of    0 to 2, and each of eb1 and eb2 represents 0, 1 or 2 in the same or    different manner. Hereupon, the sum of b1 and b2 is 2 or less),    —S(O)_(em)—(CH═CH)—, —(CH═CH)—S(O)_(em)—,-   (3) —(CH₂)_(ed1)— (de1 represents 1, 2 or 3), —CH₂—(CH═CH)—,    —(CH═CH)—CH₂—, —CH═CH—, —CH═,-   (4) —(CH₂)_(e1)—NH—(CH₂)e₂— (each of e1 and e2 represents 0, 1 or 2    in the same or different manner. Hereupon, the sum of e1 and e2 is 2    or less), —NH—(CH═CH)—, —(CH═CH)—NH—,    —(CH₂)_(e6)—(N═CH)—(CH₂)_(e7)—, —(CH₂)_(e7)—(CH═N)—(CH₂)_(e6)—    (either of e6 and e7 represents 0, and the other represents 0 or 1),    —(CH₂)_(e8)—(N═N)—(CH₂)_(e9)— (either of e8 and e9 represents 0, and    the other represents 0 or 1) or the like. Specifically, the bivalent    group is exemplified by, for example, a bivalent group such as —O—,    —O—CH₂—, —O—CH₂—CH₂—, —O—CH═CH—, —S(O)_(em)— (em represents an    integer of 0 to 2), —S(O)_(em)—CH₂— (em represents an integer of 0    to 2), —S(O)_(em)—CH₂—CH₂— (em represents an integer of 0 to 2),    —S(O)_(em)—(CH═CH)—, (em represents an integer of 0 to 2), —CH₂—,    —(CH₂)₂—, —(CH₂)₃—, —CH═, —CH═CH—, —CH═CH—CH₂—, —CH₂—CH═CH—, —NH—,    —N═CH—, —CH═N—, —N═N-(respectively, the bonding represented starts    from ring A) or the like.

In addition, the bivalent group may have a substituent, and thesubstituent is exemplified by a group similar to “the substituent” whichmay be possessed by “a 5- to 6-membered cyclic ring” of “a 5- to6-membered cyclic ring which may be substituted”, which is representedby R^(e1), oxo and the like, where a lower (C₁₋₃) alkyl (for example,methyl, ethyl, propyl or the like), phenyl, oxo, a hydroxyl group or thelike is particularly preferable. Furthermore, the bivalent group may be—O—C(O)— (the bonding represented starts from ring A) or the like. Thesubstituent for such a bivalent group may be present at any same ordifferent positions of 1 to 4 (preferably, 1 to 2). The substituentposition may be any position that is substitutable to the bivalentgroup.

As the bivalent group which is represented by Y^(e), a group such as—Y^(e′)—(CH₂)_(em′)— (Y^(e′) is —S(O)_(em)— (em is an integer of 0 to2), —O—, —NH— or —CH₂—, and em′ is an integer of 0 to 2), —CH═, —CH═CH—,—N═CH—, —(CH₂)_(em′)—Y^(e)—(Y^(e′) is —S(O)_(em)— (em is an integer of 0to 2), —O—, —NH— or —CH₂—, and em′ is an integer of 0 to 2), —CH═N— orthe like, with starting the bonding representd from ring A^(e), ispreferable, where a group such as —Y^(e′)—(CH₂)_(em′)— (Y^(e′) is—S(O)_(em)— (em is an integer of 0 to 2), —O—, —NH— or —CH₂—, and em′ isan integer of 0 to 2), —CH═, —CH═CH—, —N═CH— or the like, with startingthe bonding representd from ring A^(e), is more preferable, and a group(ring B^(e) is a 5- to 7-membered ring which may be substituted) such as—Y^(e′)—(CH₂)₂— (Y^(e)′ represents —S(O)_(em)— (em represents an integerof 0 to 2), —O—, —NH— or —CH₂—), with starting the bonding representdfrom ring A^(e), is most preferable.

“The substituent” which may be possessed by “a 5- to 7-membered cyclicring” of “a 5- to 7-membered cyclic ring which may be substituted”,which is represented by B^(e), is exemplified by a group similar to “thesubstituent” which may be possessed by “a 5- to 6-membered cyclic ring”of “a 5- to 6-membered cyclic ring which may be substituted”, which isrepresented by R^(e1). Also, such a substituent for B^(e) may be presentat any positions of 1 to 4 (preferably, 1 to 2) of the same or differentrings, but it is preferable that the position of E_(e3) isunsubstituted.

In the above-mentioned formula (eI), it is preferable that each ofE_(e3) and E_(e4) is the carbon atom that may be substituted(preferably, the carbon atom which is not substituted), and eb is adouble bond.

In the above-mentioned formula (eI), “a bivalent cyclic ring group”representd by Z^(e1) is exemplified by a group which is formed byremoving two hydrogen atoms from a group similar to “a 5- to 6-memberedcyclic ring” of “a 5- to 6-membered cyclic ring which may besubstituted”, or the like, where a bivalent cyclic ring group, which isformed by removing two hydrogen atoms from benzene, furan, thiophene,pyridine, cyclopentane, cyclohexane, pyrrolidine, piperidine,piperazine, morpholine, thiomorpholine, tetrahydropyran or the like, ismore preferable, and a bivalent cyclic ring group, which is formed byremoving two hydrogen atoms from benzene, cyclohexane or piperidine(preferably, benzene) is most preferably used.

“A bivalent cyclic ring group” representd by Z^(e1) may have asubstituent similar to “a substituent” which is possessed by “a 5- to6-membered cyclic ring” of “a 5- to 6-membered cyclic ring which may besubstituted”, but it is preferable not to have a substituent other thanX^(e2) and Z^(e2), and also it is preferable that the substitutionposition for Z^(e2) is para to X^(e2) in the case where Z^(e1) is a6-membered, bivalent cyclic ring group (preferably, phenylene).

In the above-mentioned formula (eI), “a bivalent group, in which thenumber of hydrogen atoms constituting the straight-chain portion is 1 to4”, which is represented by Z^(e2), is exemplified by a bivalent groupwhich has a hydrocarbon chain having the carbon number of 1 to 4, whichmay be substituted (for example, a C₁₋₄ alkylene, a C₂₋₄ alkenylene orthe like, preferably a C₁₋₃ alkylene, more preferably methylene), or thelike.

A bivalent group, which is represented by Z^(e2), may be any grouphaving a bivalent chain, in which the number of atoms constituting thestraight-chain portion is 1 to 4, and is exemplified by, for example, analkylene chain represented by —(CH₂)_(ek1)— (ek1 is an integer of 1 to4), an alkenylene chain represented by —(CH₂)_(ek2)—(CH═CH)—(CH₂)_(ek3)—(each of ek2 and ek3 represents an integer of 0, 1 or 2 in the same ordifferent manner. Hereupon, the sum of ek2 and ek3 is 2 or less) or thelike.

A bivalent group, which is represented by X^(e1), X^(e2) and Z^(e2), mayhave a substituent at an optional position (preferably, on the carbonatom), where such a substituent may be any one that is capable of beingbonded to a bivalent chain constituting the straight-chain portion, isexemplified by, for example, a lower (C₁₋₆) alkyl (for example, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, hexyl or the like), a lower (C₃₋₇)cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl or the like), formyl, a lower (C₂₋₇) alkanoyl(for example, acetyl, propionyl, butyryl or the like), a phosphono groupwhich may be esterified, the carboxyl group which may be esterified, thehydroxyl group, oxo or the like, where preferably a lower alkyl havingthe carbon number of 1 to 6 (preferably a C₁₋₃ alkyl), the hydroxylgroup, oxo or the like is exemplified.

The phosphono group which may be esterified is exemplified by a grouprepresented by —P(O)(OR^(e7))(OR^(e8)) [wherein each of R^(e7) andR^(e8) is hydrogen, an alkyl group having the carbon number of 1 to 6 ora cycloalkyl group having the carbon number of 3 to 7, and may be bondedtogether to form a 5- to 7-membered cyclic ring].

In the above-mentioned formula, an alkyl group having the carbon numberof 1 to 6, which is represented by R^(e7) and R^(e8), is exemplified bymethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl or the like, and acycloalkyl having the carbon number of 3 to 7 is exemplified bycyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or thelike), where a lower alkyl having the carbon number of 1 to 6 isexemplified preferably, and a lower alkyl having the carbon number of 1to 3 is exemplified more preferably. R^(e7) and R^(e8) may be the sameor different, but it is preferable to be the same. Also, in the casewhere R^(e7) and R^(e8) are bonded together to form a 5- to 7-memberedcyclic ring, R^(e7) and R^(e8) are bonded together to form astraight-chained C₂₋₄ alkylene side chain represented by —(CH₂)₂—,—(CH₂)₃—, —(CH₂)₄—. The side chain may have substituents, and such asubstituent is exemplified by, for example, the hydroxyl group, ahalogen or the like.

The carboxyl group, which is esterified for the carboxyl group which maybe esterified, is exemplified by a group, wherein the carboxyl group isbonded with an alkyl group having the carbon number of 1 to 6 or acycloalkyl group having the carbon number of 3 to 7, such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl,tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl or the like.

A bivalent group, which is represented by Z^(e2), is exemplified by aC₁₋₃ alkylene that may be substituted, where a C₁₋₃ alkylene that may besubstituted with a C₁₋₃ alkyl, the hydroxyl group or oxo is morepreferable.

Furthermore, as for a bivalent group, which is represented by Z^(e2), agroup represented by -Z^(e′)—(CH₂)en- or —(CH₂)en-Z^(e′)— (Z^(e′) is—CH(OH)—, —C(O)— or —CH₂—, en is an integer of 0 to 2 and each methylenegroup may have 1 to 2 groups of the same or different substituent), withstarting from the benzene ring, is preferable, a group represented by-Z^(e′)—(CH₂)en- (Z^(e′) represents —CH(OH)—, —C(O)— or —CH₂—, enrepresents an integer of 0 to 2 (preferably, en is 0) and each methylenegroup may have 1 to 2 groups of the same or different substituents),with starting from the benzene ring, is more preferable and methylene ismost preferable.

In the above-mentioned formula (eI), “an amino group” of “an amino groupwhich may be substituted, where the nitrogen atom may be converted intoa quaternary ammonium or the N-oxide” represented by R^(e2), isexemplified by an amino group which may have 1 to 2 substituents, anamino group which has 3 substituents, where the nitrogen atom may beconverted into a quaternary ammonium, or the like. In the case where thesubstituents on the nitrogen atom are 2 or more, these substituents maybe the same or different, and in the case where the substituents on thenitrogen atom are 3, the amino group may be of any type of —N⁺(R^(e))₃,—N⁺(R^(e))₂R^(e), N⁺R^(e)R^(e′)R^(e″) (each of R^(e), R^(e′) and R^(e″)is hydrogen or a substituent in a different manner) In addition, acounter anion for the amino group, in which the nitrogen atom isconverted into a quaternary ammonium, is exemplified by, in addition toan anion of a halogen atom (for example, Cl⁻, Br⁻, I⁻ or the like) orthe like, an anion derived from an inorganic acid such as hydrochloricacid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid andthe like, an anion derived from an organic acid such as formic acid,acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaricacid, maleic acid, citric acid, succinic acid, malic acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid andthe like and an anion derived from an acidic amino acid such as asparticacid, glutamic acid and the like, where Cl⁻, Br⁻, I⁻ or the like is morepreferable.

Examples of substituents for the amino group include substituents suchas,

-   (1) an alkyl which may be substituted (for example, a C₁₋₁₀ alkyl    such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,    sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl,    octyl, nonyl, decyl or the like, preferably a lower (C₁₋₆) alkyl or    the like is exemplified);-   (2) a cycloalkyl which may be substituted (for example, a C₃₋₈    cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    cycloheptyl, cyclooctyl or the like is exemplified);-   (2-1) the cycloalkyl contains one heteroatom selected from the    sulfur atom, the oxygen atom and the nitrogen atom, and may form    oxirane, thiolan, aziridine, tetrahydrofuran, tetrahydrothiophene,    pyrrolidine, tetrahydropyran, tetrahydrothiopyran,    tetrahydrothiopyran 1-oxide, piperidine or the like (preferably, a    6-membred ring such as tetrahydropyran, tetrahydrothiopyran,    piperidine or the like), where the binding position with the amino    group is preferably position 3 or position 4 (preferably, position    4);-   (2-2) also, the cycloalkyl may condensed with the benzene ring to    form an indane (for example, indan-1-yl, indan-2-yl or the like),    tetrahydronaphthalene, (for example, tetrahydronaphthalen-5-yl,    tetrahydronaphthalen-6-yl or the like) or the like (preferably,    indane, etc.);-   (2-3) furthermore, the cycloalkyl may be crosslinked via a    straight-chained, atom chain having the carbon number of 1 to 2 to    form a crosslinked, cyclic hydrocarbon residue such as    bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl,    bicyclo[3.2.2]nonyl or the like (preferably, a cycloalkyl having a    crosslink via a straight-chained, atom chain having the carbon    number of 1 to 2, or the like, more preferably bicyclo[2.2.1]heptyl    or the like);-   (3) an alkenyl which may be substituted (for example, an alkenyl    which has the carbon number of 2 to 10 such as allyl, crotyl,    2-pentenyl, 3-hexenyl or the like, preferably a lower (C₂₋₆)    alkenyl, or the like is exemplified);-   (4) a cycloalkenyl which may be substituted (for example, an    cycloalkenyl which has the carbon number of 3 to 7 such as    2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl,    2-cyclohexenylmethyl or the like, or the like is exemplified);-   (5) an aralkyl which may be substituted (for example, a phenyl-C₁₋₄    alkyl (for example, benzyl, phenethyl or the like) or the like is    exemplified);-   (6) formyl or an acyl which may be substituted (for example, an    alkanoyl which has the carbon number of 2 to 4 (for example, acetyl,    propionyl, butyryl, isobutyryl or the like), an alkylsulfonyl which    has the carbon number of 1 to 4 (for example, methanesulfonyl,    ethanesulfonyl or the like), an alkoxycarbonyl which has the carbon    number of 1 to 4 (methoxycarbonyl, ethoxycarbonyl,    tert-butoxycarbonyl or the like), an aralkyloxycarbonyl which has    the carbon number of 7 to 10 (for example, benzyloxycarbonyl or the    like) or the like is exemplified);-   (7) an aryl which may be substituted (for example, phenyl, naphthyl    or the like is exemplified); and-   (8) a heterocyclic ring group which may be substituted (a group    which is formed by removing one hydrogen atom from a 5- to    6-membered, aromatic heterocyclic ring, which contains 1 to 4    heteroatoms of 1 to 2 kinds selected from the nitrogen atom, the    sulfur atom and the oxygen atom, such as furan, thiophene, pyrrole,    imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole,    tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole or    the like, a group which is formed by removing one hydrogen atom from    a 5- to 6-membered, non-aromatic heterocyclic ring, which contains 1    to 4 heteroatoms of 1 to 2 kinds selected from the nitrogen atom,    the sulfur atom and the oxygen atom, such as tetrahydrofuran,    tetrahydrothiophene, dithiolan, oxathiolan, pyrrolidine, pyrroline,    imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine,    piperazine, oxazine, oxadiazine, thiazine, thiadiazine, morpholine,    thiomorpholine, pyran, tetrahydropyran or the like, or the like;    preferably, a group, which is formed by removing one hydrogen atom    from a 5- to 6-membered, non-aromatic heterocyclic ring, or the    like; and more preferably, a group, which is formed by removing one    hydrogen atom from a 5- to 6-membered, non-aromatic heterocyclic    ring, which has one heteroatom, such as tetrahydrofuran, piperidine,    tetrahydropyran, tetrahydrothiopyran or the like) and the like. In    addition, the substituents of the amino group may be bonded each    other to form a 5- to 7-membered, cyclic amino such as piperidine,    piperazine, morpholine, thiomorpholine or the like.

Examples of the substituents which may be possessed by (1) an alkylwhich may be substituted, (2) a cycloalkyl which may be substituted, (3)an alkenyl which may be substituted, (4) a cycloalkenyl which may besubstituted, (5) an aralkyl which may be substituted, (6) an acyl whichmay be substituted, (7) an aryl which may be substituted and (8) aheterocyclic ring group which may be substituted, which are describedabove, include a halogen (for example, fluorine, chlorine, bromine,iodine or the like), a lower (C₁₋₄) alkyl which may be halogenated, aC₁₋₄ alkoxyl which may be halogenated (for example, methoxy, ethoxy,propoxy, butoxy, trifluoromethoxy, trifluoroethoxy or the like), a C₁₋₄alkylenedioxy (for example, —O—CH₂—O—, —O—CH₂—CH₂—O— or the like),formyl, a C₂₋₄ alkanoyl (for example, acetyl, propionyl or the like), aC₁₋₄ alkylsulfonyl (for example, methanesulfonyl, ethanesulfonyl or thelike), a phenyl-lower (C₁₋₄) alkyl, a C₃₋₇ cycloalkyl, cyano, nitro, ahydroxyl group, a thiol group which may be substituted (for example,thiol, a C₁₋₄ alkylthio or the like), an amino group which may besubstituted (for example, amino, a mono-C₁₋₄ alkylamino, a di-C₁₋₄alkylamino, a 5- to 6-membered cyclic ring amino such astetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine,pyrrole, imidazole or the like, or the like), the carboxyl group whichmay be esterified or amidated (for example, carboxyl, a C₁₋₄alkoxycarbonyl, carbamoyl, a mono-C₁₋₄ alkylcarbamoyl, a di-C₁₋₄alkylcarbamoyl or the like), a lower (C₁₋₄) alkoxycarbonyl, a lower(C₇₋₁₀) aralkyloxycarbonyl, the oxo group (preferably, a halogen, alower (C₁₋₄) alkyl which may be halogenated, a C₁₋₄ alkoxyl which may behalogenated, a phenyl-lower (C₁₋₄) alkyl, a C₃₋₇ cycloalkyl, cyano, ahydroxyl group or the like) and the like, where the number of thesubstituents is preferably 1 to 3.

In the above-mentioned formula (eI), “an amino group which may besubstituted, where the nitrogen atom may be converted into a quaternaryammonium or the N-oxide” representd by R^(e2), is preferably an aminogroup which may have 1 to 3 substituents selected from,

-   (1) a straight-chained or branched, lower (C₁₋₆) alkyl which may    have 1 to 3 groups of a halogen, cyano, a hydroxyl group or a C₃₋₇    cycloalkyl;-   (2) a C₅₋₈ cycloalkyl which may have 1 to 3 groups of a halogen, a    lower (C₁₋₄) alkyl which may be halogenated or a phenyl-lower (C₁₋₄)    alkyl, may contain one heteroatom selected from the sulfur atom, the    oxygen atom and the nitrogen atom, may be condensed with the benzene    ring and may be crosslinked via a straight-chained, atom chain    having the carbon number of 1 to 2, (for example, cyclopentyl,    cyclohexyl, cycloheptyl cyclooctyl, tetrahydropyranyl,    tetrahydrothiapyranyl, piperidinyl, indanyl, tetrahydronaphthalenyl,    bicyclo[2.2.1]heptyl or the like);-   (3) a phenyl-lower (C₁₋₄) alkyl which may have 1 to 3 groups of a    halogen, a lower (C₁₋₄) alkyl which may be halogenated or a C₁₋₄    alkoxyl which may be halogenated;-   (4) a phenyl which may have 1 to 3 groups of a halogen, a lower    (C₁₋₄) alkyl which may be halogenated or a C₁₋₄ alkoxyl which may be    halogenated; and-   (5) a 5- to 6-membered, aromatic heterocyclic ring which may have 1    to 3 groups of a halogen, a lower (C₁₋₄) alkyl which may be    halogenated, a C₁₋₄ alkoxy which may be halogenated, a lower (C₁₋₄)    alkoxy-(C₁₋₄) lower alkoxy which may be halogenated, a phenyl-lower    (C₁₋₄) alkyl, cyano or the hydroxyl (for example, a group which is    formed by removing one hydrogen atom from furan, thiophene, pyrrole,    pyridine or the like).

In the above-mentioned formula (eI), “a nitrogen-containing,heterocyclic ring” of “a nitrogen-containing, heterocyclic group whichmay be substituted and may contain the sulfur atom or the oxygen atom asa ring-constituting atom, where the nitrogen atom may be converted intoa quaternary ammonium or the N-oxide” is exemplified by a 5- to6-membered, aromatic heterocyclic ring, which may contain, in additionto one nitrogen atom, 1 to 3 heteroatoms of 1 to 2 kinds selected fromthe nitrogen atom, the sulfur atom and the oxygen atom, such as pyrrole,imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole,tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole or thelike, a 5- to 8-membered, non-aromatic heterocyclic ring, which maycontain, in addition to one nitrogen atom, 1 to 3 hetero atoms of 1 to 2kinds selected from the nitrogen atom, the sulfur atom and the oxygenatom, such as pyrrolidine, pyrroline, imidazolidine, imidazoline,pyrazolidine, pyrazoline, piperidine, piperazine, oxazine, oxadiazine,thiazine, thiadiazine, morpholine, thiomorpholine, azacycloheptane,azacyclooctane (azokane) or the like, or the like, where each of thesenitrogen-containing, heterocyclic rings may be crosslinked via astraight-chained, atom chain having the carbon number of 1 to 2 and mayform a crosslinked, nitrogen-containing, heterocyclic ring such asazabicyclo[2.2.1]heptane, azabicyclo[2.2.2]octane (quinuclidine) or thelike (preferably, piperidine, which may have a crosslink via astraight-chained, atom chain having the carbon number of 1 to 2, or thelike).

Among the specific examples of the above-mentioned nitrogen-containingheterocyclic ring, pyridine, imidazole, pyrrolidine, piperidine,piperazine, morpholine, thiomorpholine and azabicyclo[2.2.2]octane(preferably, 6-membered, cyclic rings) are preferable.

The nitrogen atom of the “nitrogen-containing heterocyclic ring” may beconverted into a quaternary ammonium, or may be oxidized. In the casewhere the nitrogen atom of the “nitrogen-containing heterocyclic ring”is converted into a quaternary ammonium, a counter anion for “thenitrogen-containing heterocyclic ring group, in which the nitrogen atomis converted into a quaternary ammonium”, is exemplified by, in additionto an anion of a halogen atom (for example, Cl⁻, Br⁻, I⁻ or the like) orthe like, an anion derived from an inorganic acid such as hydrochloricacid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid andthe like, an anion derived from an organic acid such as formic acid,acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaricacid, maleic acid, citric acid, succinic acid, malic acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid andthe like and an anion derived from an acidic amino acid such as asparticacid, glutamic acid and the like, where Cl⁻, Br⁻, I⁻ or the like is morepreferable.

The “nitrogen-containing heterocyclic ring” may be bonded with abivalent group, which is represented by Z^(e2), via either of the carbonatom or the nitrogen atom and may be bonded on the carbon atomconstituting the cyclic ring, as in the case of 2-pyridyl, 3-pyridyl,2-piperidyl or the like, whereas a bonding as in the case of

or the like is preferable.

Examples of substituents of the “nitrogen-containing heterocyclic ring”include a halogen (for example, fluorine, chlorine, bromine, iodine orthe like), a lower (C₁₋₄) alkyl which may be substituted, a lower (C₁₋₄)alkoxyl which may be substituted, a phenyl which may be substituted, amono- or diphenyl-lower (C₁₋₄) alkyl which may be substituted, a C₃₋₇cycloalkyl which may be substituted, cyano, nitro, a hydroxyl group, athiol group which may be substituted (for example, thiol, a C₁₋₄alkylthio or the like), an amino group which may be substituted (forexample, amino, a mono-C₁₋₄ alkylamino, a di-C₁₋₄ alkylamino, a 5- to6-membered cyclic ring amino such as tetrahydropyrrole, piperazine,piperidine, morpholine, thiomorpholine, pyrrole, imidazole or the like,or the like), the carboxyl group which may be esterified or amidated(for example, carboxyl, a C₁₋₄ alkoxycarbonyl, carbamoyl, a mono-C₁₋₄alkylcarbamoyl, a di-C₁₋₄ alkylcarbamoyl or the like), a lower (C₁₋₄)alkoxycarbonyl, formyl, a (C₂₋₄) alkanoyl, a lower (C₁₋₄) alkylsulfonyl,a heterocyclic ring group which may be substituted (e.g. a group whichis formed by removing one hydrogen atom from a 5- to 6-membered,aromatic heterocyclic ring, which contains 1 to 4 heteroatoms of 1 to 2kinds selected from the nitrogen atom, the sulfur atom and the oxygenatom, such as furan, thiophene, pyrrole, imidazole, pyrazole, thiazole,oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine,pyrimidine, pyridazine, triazole or the like, a group which is formed byremoving one hydrogen atom from a 5- to 6-membered, non-aromaticheterocyclic ring, which contains 1 to 4 heteroatoms of 1 to 2 kindsselected from the nitrogen atom, the sulfur atom and the oxygen atom,such as tetrahydrofuran, tetrahydrothiophene, dithiolan, oxathiolan,pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine,pyrazoline, piperidine, piperazine, oxazine, oxadiazine, thiazine,thiadiazine, morpholine, thiomorpholine, pyran, tetrahydropyran,tetrahydrothiopyran or the like, or the like, where the number of thesubstituents is preferably 1 to 3. Also, the nitrogen in the“nitrogen-containing heterocyclic ring” may be oxidized.

Examples of the substituents, which may be possessed by “a lower (C₁₋₄)alkyl which may be substituted”, “a lower (C₁₋₄) alkoxyl which may besubstituted”, “a phenyl which may be substituted”, “a mono- ordiphenyl-lower (C₁₋₄) alkyl which may be substituted”, “a C₃₋₇cycloalkyl which may be substituted” and “a heterocyclic ring group:which may be substituted”, as the substituents which may be possessed bythe “nitrogen-containing heterocyclic ring”, include, for example, ahalogen (for example, fluorine, chlorine, bromine, iodine or the like),a lower (C₁₋₄) alkyl which may be halogenated, a lower (C₃₋₁₀)cycloalkyl, a lower (C₃₋₁₀) cycloalkenyl, a C₁₋₄ alkoxy which may behalogenated (for example, methoxy, ethoxy, trifluoromethoxy,trifluoroethoxy or the like), formyl, a C₂₋₄ alkanoyl (for example,acetyl, propionyl or the like), a C₁₋₄ alkylsulfonyl (for example,methanesulfonyl, ethanesulfonyl or the like), a C₁₋₃ alkylenedioxy (forexample, methylenedioxy, ethylenedioxy or the like), cyano, nitro, thehydroxyl group, the thiol group which may be substituted (for example,thiol, a C₁₋₄ alkylthio or the like), an amino group which may besubstituted (for example, amino, a mono-C₁₋₄ alkylamino, a di-C₁₋₄alkylamino, a 5- to 6-membered cyclic ring amino such astetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine,pyrrole, imidazole or the like, or the like), the carboxyl group whichmay be esterified or amidated (for example, carboxyl, a C₁₋₄alkoxycarbonyl, carbamoyl, a mono-C₁₋₄ alkylcarbamoyl, a di-C₁₋₄alkylcarbamoyl or the like), a lower (C₁₋₄) alkoxycarbonyl and the like,where the number of the substituents is preferably 1 to 3.

In the above-mentioned formula (eI), the substituent, which may bepossessed by “a nitrogen-containing heterocyclic ring” of “anitrogen-containing heterocyclic ring group which may be substituted andmay contain the sulfur atom or the oxygen atom as a ring-constitutingatom, where the nitrogen atom may be converted into a quaternaryammonium or the N-oxide” is exemplified preferably by (1) a halogen, (2)cyano, (3) a hydroxyl group, (4) a carboxyl group, (5) a lower (C₁₋₄)alkoxycarbonyl, (6) a lower (C₁₋₄) alkyl which may be substituted with ahalogen, a hydroxyl group or a lower (C₁₋₄) alkoxy, (7) a lower (C₁₋₄)alkoxy which may be substituted with a halogen, the hydroxyl group or alower (C₁₋₄) alkoxy, (8) a phenyl which may be substituted with ahalogen, a lower (C₁₋₄) alkyl, a hydroxyl group, a lower (C₁₋₄) alkoxyor a C₁₋₃ alkylenedioxy, (9) a mono- or diphenyl-lower (C₁₋₄) alkylwhich may be substituted with a halogen, a lower (C₁₋₄) alkyl, thehydroxyl group, a lower (C₁₋₄) alkoxy or a C₁₋₃ alkylenedioxy, (10) agroup which is formed by removing one hydrogen atom from a 5- to6-membered aromatic heterocyclic ring, such as furan, thiophene,pyrrole, pyridine or the like, or the like.

In the above-mentioned formula (eI), “a group which is bonded via thesulfur atom”, which is represented by R^(e2), is exemplified by a grouprepresented by —S(O)em-R^(eS) (wherein em represents an integer of 0 to2 and R^(eS) is a substituent). In the above-mentioned formula, examplesof the substituent representd by R^(eS) include, for example,

-   (1) an alkyl which may be substituted (for example, a C₁₋₁₀ alkyl    such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,    sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl,    octyl, nonyl, decyl or the like, preferably a lower (C₁₋₆) alkyl, or    the like is exemplified);-   (2) a cycloalkyl which may be substituted (for example, a C₃₋₇    cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    cycloheptyl or the like is exemplified);-   (3) an aralkyl which may be substituted (for example, a phenyl-C₁₋₄    alkyl (for example, benzyl, phenethyl or the like) or the like is    exemplified); and-   (4) an aryl which may be substituted (for example, phenyl, naphthyl    or the like is exemplified), where examples of the substituents    which may be possessed by (1) an alkyl which may be substituted, (2)    a cycloalkyl which may be substituted, (3) an aralkyl which may be    substituted and (4) an aryl which may be substituted, which are    described above, include a halogen (for example, fluorine, chlorine,    bromine, iodine or the like), nitro, cyano, a hydroxyl group, a    thiol group which may be substituted (for example, thiol, a C₁₋₄    alkylthio or the like), an amino group which may be substituted (for    example, amino, a mono-C₁₋₄ alkylamino, a di-C₁₋₄ alkylamino, a 5-    to 6-membered cyclic ring amino such as tetrahydropyrrole,    piperazine, piperidine, morpholine, thiomorpholine, pyrrole,    imidazole or the like, or the like), the carboxyl group which may be    esterified or amidated (for example, carboxyl, a C₁₋₄    alkoxycarbonyl, carbamoyl, a mono-C₁₋₄ alkylcarbamoyl, a di-C₁₋₄    alkylcarbamoyl or the like), a C₁₋₄ alkyl which may be halogenated    (for example, trifluoromethyl, methyl, ethyl or the like), a C₁₋₄    alkoxy which may be halogenated (for example, methoxy, ethoxy,    trifluoromethoxy, trifluoroethoxy or the like), formyl, a C₂₋₄    alkanoyl (for example, acetyl, propionyl or the like), a C₁₋₄    alkylsulfonyl (for example, methanesulfonyl, ethanesulfonyl or the    like) or the like, where the number of the substituents is    preferably 1 to 3.

In the above-mentioned formula (eI), “the hydrocarbon group” for thehydrocarbon group which may be substituted, which is represented byR^(e5′) and R^(e6′), in “a group represented by formula

wherein ek represents 0 or 1, the phosphorus atom may form a phosphoniumsalt when ek is 0, and each of R^(e5′) and R^(e6′) is a hydrocarbongroup which may be substituted, a hydroxyl group which may besubstituted or an amino group which may be substituted, preferably, thehydrocarbon group which may be substituted or an amino group which maybe substituted; more preferably the hydrocarbon group which may besubstituted, and R^(e5′) and R^(e6′) may bind each other to form acyclic ring group together with the adjacent phosphorus atom”, which isrepresented by R^(e2), is exemplified by,

-   (1) an alkyl which may be substituted (for example, a C₁₋₁₀ alkyl    such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,    sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl,    octyl, nonyl, decyl or the like, preferably a lower (C₁₋₆) alkyl, or    the like is exemplified);-   (2) a cycloalkyl which may be substituted (for example, a C₃₋₇    cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    cycloheptyl or the like);-   (3) an alkenyl which may be substituted (for example, an alkenyl    which has the carbon number of 2 to 10 such as allyl, crotyl,    2-pentenyl, 3-hexenyl or the like, preferably a lower (C₂₋₆)    alkenyl, or the like is exemplified);-   (4) a cycloalkenyl which may be substituted (for example, an    cycloalkenyl which has the carbon number of 3 to 7 such as    2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl,    2-cyclohexenylmethyl or the like, or the like is exemplified);-   (5) an alkinyl which may be substituted (for example, an alkinyl    which has the carbon number of 2 to 10 such as ethinyl, 1-propinyl,    2-propinyl, 1-butinyl, 2-pentinyl, 3-hexinyl or the like, preferably    a lower (C₂₋₆) alkinyl, or the like is exemplified);-   (6) an aralkyl which may be substituted (for example, a phenyl-C₁₋₄    alkyl (for example, benzyl, phenethyl or the like) or the like is    exemplified); and-   (7) an aryl which may be substituted (for example, phenyl, naphthyl    or the like is exemplified), where examples of the substituents    which may be possessed by (1) an alkyl which may be substituted, (2)    a cycloalkyl which may be substituted, (3) an alkenyl which may be    substituted, (4) a cycloalkenyl which may be substituted, (5) an    alkinyl which may be substituted, (6) an aralkyl which may be    substituted and (7) an aryl which may be substituted, which are    described above, include a halogen (for example, fluorine, chlorine,    bromine, iodine or the like), nitro, cyano, a hydroxyl group, a    thiol group which may be substituted (for example, thiol, a C₁₋₄    alkylthio or the like), an amino group which may be substituted (for    example, amino, a mono-C₁₋₄ alkylamino, a di-C₁₋₄ alkylamino, a 5-    to 6-membered cyclic ring amino such as tetrahydropyrrole,    piperazine, piperidine, morpholine, thiomorpholine, pyrrole,    imidazole or the like, or the like), the carboxyl group which may be    esterified or amidated (for example, carboxyl, a C₁₋₄    alkoxycarbonyl, carbamoyl, a mono-C₁₋₄ alkylcarbamoyl, a di-C₁₋₄    alkylcarbamoyl or the like), a C₁₋₄ alkyl which may be halogenated    (for example, trifluoromethyl, methyl, ethyl or the like), a C₁₋₄    alkoxy which may be halogenated (for example, methoxy, ethoxy,    trifluoromethoxy, trifluoroethoxy or the like), formyl, a C₂₋₄    alkanoyl (for example, acetyl, propionyl or the like), a C₁₋₄    alkylsulfonyl (for example, methanesulfonyl, ethanesulfonyl or the    like) or the like, where the number of the substituents is    preferably 1 to 3.

The hydroxyl group which may be substituted, which is represented byR^(e5′) and R^(e6′), is exemplified by a hydroxyl group which may besubstituted by, for example, (1) an alkyl which may be substituted (forexample, a C₁₋₁₀ alkyl such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl,heptyl, octyl, nonyl, decyl or the like, preferably a lower (C₁₋₆)alkyl, or the like is exemplified);

-   (2) a cycloalkyl which may be substituted (for example, a C₃₋₇    cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    cycloheptyl or the like);-   (3) an alkenyl which may be substituted (for example, an alkenyl    which has the carbon number of 2 to 10 such as allyl, crotyl,    2-pentenyl, 3-hexenyl or the like, preferably a lower (C₂₋₆)    alkenyl, or the like is exemplified);-   (4) a cycloalkenyl which may be substituted (for example, an    cycloalkenyl which has the carbon number of 3 to 7 such as    2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl,    2-cyclohexenylmethyl or the like, or the like is exemplified);-   (5) an aralkyl which may be substituted (for example, a phenyl-C₁₋₄    alkyl (for example, benzyl, phenethyl or the like) or the like is    exemplified);-   (6) formyl or an acyl which may be substituted (for example, an    alkanoyl which has the carbon number of 2 to 4 (for example, acetyl,    propionyl, butyryl, isobutyryl or the like), an alkylsulfonyl which    has the carbon number of 1 to 4 (for example, methanesulfonyl,    ethanesulfonyl or the like) or the like is exemplified); and-   (7) an aryl which may be substituted (for example, phenyl, naphthyl    or the like is exemplified).

Examples of the substituents which may be possessed by (1) an alkylwhich may be substituted, (2) a cycloalkyl which may be substituted, (3)an alkenyl which may be substituted, (4) a cycloalkenyl which may besubstituted, (5) an aralkyl which may be substituted, (6) an acyl whichmay be substituted and (7) an aryl which may be substituted, which aredescribed above, include a halogen (for example, fluorine, chlorine,bromine, iodine or the like), nitro, cyano, the hydroxyl group, thethiol group which may be substituted (for example, thiol, a C₁₋₄alkylthio or the like), an amino group which may be substituted (forexample, amino, a mono-C₁₋₄ alkylamino, a di-C₁₋₄ alkylamino, a 5- to6-membered cyclic ring amino such as tetrahydropyrrole, piperazine,piperidine, morpholine, thiomorpholine, pyrrole, imidazole or the like,or the like), the carboxyl group which may be esterified or amidated(for example, carboxyl, a C₁₋₄ alkoxycarbonyl, carbamoyl, a mono-C₁₋₄alkylcarbamoyl, a di-C₁₋₄ alkylcarbamoyl or the like), a C₁₋₄ alkylwhich may be halogenated (for example, trifluoromethyl, methyl, ethyl orthe like), a C₁₋₄ alkoxy which may be halogenated (for example, methoxy,ethoxy, trifluoromethoxy, trifluoroethoxy or the like), formyl, a C₂₋₄alkanoyl (for example, acetyl, propionyl or the like), a C₁₋₄alkylsulfonyl (for example, methanesulfonyl, ethanesulfonyl or the like)and the like, where the number of the substituents is preferably 1 to 3.

Also, in the above-mentioned formula, R^(e5′) and R^(e6′) may bind eachother to form a cyclic ring group together with the adjacent phosphorusatom (preferably, a 5- to 7-membered cyclic ring). Such a cyclic ringgroup may have substituents and examples of the substituents include ahalogen (for example, fluorine, chlorine, bromine, iodine or the like),nitro, cyano, a hydroxyl group, a thiol group which may be substituted(for example, thiol, a C₁₋₄ alkylthio or the like), an amino group whichmay be substituted (for example, amino, a mono-C₁₋₄ alkylamino, adi-C₁₋₄ alkylamino, a 5- to 6-membered cyclic amino such astetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine,pyrrole, imidazole or the like, or the like), the carboxyl group whichmay be esterified or amidated (for example, carboxyl, a C₁₋₄alkoxycarbonyl, carbamoyl, a mono-C₁₋₄ alkylcarbamoyl, a di-C₁₋₄alkylcarbamoyl or the like), a C₁₋₄ alkyl which may be halogenated (forexample, trifluoromethyl, methyl, ethyl or the like), a C₁₋₄ alkoxywhich may be halogenated (for example, methoxy, ethoxy,trifluoromethoxy, trifluoroethoxy or the like), formyl, a C₂₋₄ alkanoyl(for example, acetyl, propionyl or the like), a C₁₋₄ alkylsulfonyl (forexample, methanesulfonyl, ethanesulfonyl or the like) and the like,where the number of the substituents is preferably 1 to 3.

In the above-mentioned formula (eI), a counter anion in the case wherethe phosphorus atom forms a phosphonium salt is exemplified by, inaddition to an anion of a halogen atom (for example, Cl⁻, Br⁻, I⁻ or thelike) or the like, an anion derived from an inorganic acid such ashydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid and the like, an anion derived from an organic acid suchas formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalicacid, tartaric acid, maleic acid, citric acid, succinic acid, malicacid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acidand the like and an anion derived from an acidic amino acid such asaspartic acid, glutamic acid and the like, where Cl⁻, Br⁻, I⁻ or thelike is more preferable.

An amino group that may be substituted, which is represented by R^(e5′)and R^(e6′), is exemplified by an amino group that may have 1 to 2groups such as,

-   (1) an alkyl which may be substituted (for example, a C₁₋₁₀ alkyl    such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,    sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl,    octyl, nonyl, decyl or the like, preferably a lower (C₁₋₆) alkyl, or    the like is exemplified);-   (2) a cycloalkyl which may be substituted (for example, a C₃₋₇    cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    cycloheptyl or the like);-   (3) an alkenyl which may be substituted (for example, an alkenyl    which has the carbon number of 2 to 10 such as allyl, crotyl,    2-pentenyl, 3-hexenyl or the like, preferably a lower (C₂₋₆)    alkenyl, or the like is exemplified);-   (4) a cycloalkenyl which may be substituted (for example, an    cycloalkenyl which has the carbon number of 3 to 7 such as    2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl,    2-cyclohexenylmethyl or the like, or the like is exemplified);-   (5) formyl or an acyl which may be substituted (for example, an    alkanoyl which has the carbon number of 2 to 4 (for example, acetyl,    propionyl, butyryl, isobutyryl or the like), an alkylsulfonyl which    has the carbon number of 1 to 4 (for example, methanesulfonyl,    ethanesulfonyl or the like) or the like is exemplified); and-   (6) an aryl which may be substituted (for example, phenyl, naphthyl    or the like is exemplified).

Examples of the substituents which may be possessed by (1) an alkylwhich may be substituted, (2) a cycloalkyl which may be substituted, (3)an alkenyl which may be substituted, (4) a cycloalkenyl which may besubstituted, (5) an acyl which may be substituted and (6) an aryl whichmay be substituted, which are described above, include a halogen (forexample, fluorine, chlorine, bromine, iodine or the like), nitro, cyano,a hydroxyl group, a thiol group which may be substituted (for example,thiol, a C₁₋₄ alkylthio or the like), an amino group which may besubstituted (for example, amino, a mono-C₁₋₄ alkylamino, a di-C₁₋₄alkylamino, a 5- to 6-membered cyclic ring amino such astetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine,pyrrole, imidazole or the like, or the like), a carboxyl group which maybe esterified or amidated (for example, carboxyl, a C₁₋₄ alkoxycarbonyl,carbamoyl, a mono-C₁₋₄ alkylcarbamoyl, a di-C₁₋₄ alkylcarbamoyl or thelike), a C₁₋₄ alkyl which may be halogenated (for example,trifluoromethyl, methyl, ethyl or the like), a C₁₋₄ alkoxy which may behalogenated (for example, methoxy, ethoxy, trifluoromethoxy,trifluoroethoxy or the like), formyl, a C₂₋₄ alkanoyl (for example,acetyl, propionyl or the like), a C₁₋₄ alkylsulfonyl (for example,methanesulfonyl, ethanesulfonyl or the like) and the like, where thenumber of the substituents is preferably 1 to 3.

The substituents for “an amidino group which may be substituted” and “aguanidino group which may be substituted” each of which is representedby R^(e2) are exemplified by substituents similar to those for “an aminogroup which may be substituted, where the nitrogen atom may be convertedinto a quaternary ammonium or the N-oxide” which is represented byR^(e2).

It is preferable that R^(e2) is (1) an amino group which may besubstituted, where the nitrogen atom may be converted into a quaternaryammonium or the N-oxide, (2) a nitrogen-containing heterocyclic ringgroup which may be substituted and may contain the sulfur atom or theoxygen atom as a ring-constituting atom, where the nitrogen atom may beconverted into a quaternary ammonium or the N-oxide, (3) an amidinogroup which may be substituted or (4) a guanidino group which may besubstituted and it is more preferable that R^(e2) is an amino groupwhich may be substituted, where the nitrogen atom may be converted intoa quaternary ammonium or the N-oxide, or the like. Also, R^(e2) may bean amidino group which may be substituted or a guanidino group which maybe substituted.

It is more preferable that R^(e2) is a group represented by—NR^(e)R^(e)″ or —N⁺R^(e)R^(e)′R^(e)″ (wherein each of R^(e), R^(e)′ andR^(e)″ represents an aliphatic hydrocarbon group (an aliphatic-chainhydrocarbon group and an aliphatic, cyclic hydrocarbon group) which maybe substituted or an alicyclic (non-aromatic) heterocyclic ring groupwhich may be substituted).

In the above-mentioned formula, “an aliphatic hydrocarbon group whichmay be substituted” and “an alicyclic heterocyclic ring group which maybe substituted”, which are representd by R^(e), R^(e)′ and R^(e)″, areexemplified by substituents similar to “an alicyclic hydrocarbon groupwhich may be substituted (for example, an alkyl, a cycloalkyl, analkenyl, a cycloalkenyl or the like, each of which may be substituted)”and “an alicyclic, heterocyclic ring group which may be substituted (forexample, a 5- to 6-membered non-aromatic heterocyclic ring which may besubstituted or the like)”, which are exemplified by as the substituentswhich may be possessed by “an amino group which may be substituted”representd by R^(e2).

Especially, as for R^(e) and R^(e)′, an aliphatic hydrocarbon groupwhich may be substituted (for example, an alkyl, an alkenyl or the like,each of which may be substituted) is preferable, a C₁₋₆ alkyl groupwhich may be substituted is more preferable and the methyl group whichmay be substituted is particularly preferable.

It is preferable that R^(e″) is an alicyclic hydrocarbon group which maybe substituted (preferably, a C₃₋₈ cycloalkyl group which may besubstituted; more preferably, a cyclohexyl which may be substituted) oran alicyclic heterocyclic ring group which may be substituted(preferably, a saturated alicyclic heterocyclic ring group which may besubstituted (preferably, a 6-membered cyclic ring group); morepreferably, tetrahydropyranyl which may be substituted,tetrahydrothiopyranyl which may be substituted or piperidyl which may besubstituted; and particularly preferably, tetrahydropyranyl which may besubstituted).

In the above formula (eIa), R^(e1) and Z^(e2) have the same meaningsgiven above.

In the above formula (eIa), a group of the formula:

represented by W^(ea) binds to adjacent groups in the following manner:

In the above formula, examples of the “5- to 6-membered aromatic ring”in the “optionally substituted 5- to 6-membered aromatic ring”represented by A^(ea) include 6-membered aromatic hydrocarbon such asbenzene, etc.; 5- to 6-membered aromatic heterocyclic ring containing 1to 3 hetero-atoms consisting of 1 to 2 kinds of hetero-atoms selectedfrom oxygen atom, sulfur atom and nitrogen atom such as furan,thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole,isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole, etc.;etc. Among others, benzene, furan, thiophene, pyridine (preferably,6-membered ring) etc. are preferable, and in particular benzene ispreferable.

Examples of the “substituents”, which the “5- to 6-membered aromaticring” in the “optionally substituted 5- to 6-membered aromatic ring”represented by A^(ea) may have, are similar to the “substituents” whichthe “5- to 6-membered ring” in the “optionally substituted 5- to6-membered ring” represented by R^(e1) may have. The number of thesubstituents for the ring A^(ea) is 1-4 (preferably 1-2), and they maybe same or different and present at any possible position (e.g. theposition of the group X^(ea) and the other positions) on the ringrepresented by A^(ea).

In the above formula, examples of the “5- to 7-membered ring” in the“optionally substituted 5- to 7-membered ring” represented by B^(e)include a 5- to 7-membered ring group of the formula:

which may have a substituent at optionally substitutable positions, etc.

In the above formula, Y^(e) has the meaning given above. One to four(preferably one or two) of these substituents for A^(ea) may be the sameor different from each other and present at any positions in the ring,and it is preferable that the carbon atom at the position ea in thegroup:

represented by W^(ea) is not substituted.

In the above formula (eIa), the amino group that may be substituted,where the nitrogen atom may be converted into a quaternary ammonium,represented by R^(e2a) include those mentioned as the amino group thatmay be substituted, where the nitrogen atom may be converted into aquaternary ammonium, represented by R^(e2).

In the above formula (eIa), the group represented by the formularepresented by R^(e2a):

wherein ek represents 0 or 1, the phosphorus atom may form a phosphoniumsalt when ek is 0, and each of R^(e5) and R^(e6) represents thehydrocarbon atom that may be substituted or an amino group that may besubstituted and R^(e5) and R^(e6) may bind each other to form a cyclicring group together with the adjacent phosphorus atom, “hydrocarbon atomthat may be substituted” or “an amino group that may be substituted”represented by R^(e5) or R^(e6) and a cyclic group in case of forming acyclic ring group by combining R^(e5) and R^(e6) together with theadjacent phosphorus atom include those mentioned as examples for theabove R^(e5′) and R^(e6′.)

In the above formula, a counter anion in case that the phosphorus atomis converted into a quaternary ammonium, is exemplified by, in additionto an anion of a halogen atom (for example, Cl⁻, Br⁻, I⁻ or the like) orthe like, an anion derived from an inorganic acid such as hydrochloricacid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid andthe like, an anion derived from an organic acid such as formic acid,acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaricacid, maleic acid, citric acid, succinic acid, malic acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid andthe like and an anion derived from an acidic amino acid such as asparticacid, glutamic acid and the like, where Cl⁻, Br⁻, I⁻ or the like is morepreferable.

As the R^(e2a), “an amino group that may be substituted, where thenitrogen atom may be converted into a quaternary ammonium and the grouprepresented by the formula:—N⁺R^(e)R^(e)′R^(e)″wherein each of R^(e),R^(e)′ and R^(e)″ is an aliphatic hydrocarbongroup which may be substituted or an alicyclic heterocyclic group whichmay be substituted are more preferable.

As a compound of the formula (eIa), a compound of the formula:

wherein R^(e1a) is an optionally substituted phenyl group or anoptionally substituted thienyl group; Y^(e″) is —CH₂—, —O—, or —S—; andR^(e), R^(e′), and R^(e″) are independently an optionally substitutedaliphatic hydrocarbon group or an optionally substituted alicyclicheterocyclic ring group, is preferable.

In the above formula, the “substituent” which may be possessed by the“phenyl group” in the “optionally substituted phenyl group” and the“thienyl group” in the “potionally substituted thienyl group”, each ofwhich is represented by R^(e1a), include those for the optionallysubstituted 5- or 6-membered cyclic ring group represented by the aboveR^(e1).

Examples of the “optionally substituted aliphatic hydrocarbon group” andthe “optionally substituted alicyclic heterocyclic ring group”represented by R^(e), R^(e)′ or R^(e)″ include those exemplified by thesubstituents for the “optionally substituted amino group” represented byR^(e2a).

Among them, as the group R^(e) or R^(e)′ an optionally substituted chainhydrocarbon group is preferable, an optionally substituted C₁₋₆ alkylgroup is more preferable, and an optionally substituted methyl group ismost preferable.

As the group R″, an optionally substituted alicyclic hydrocarbon group(more preferably, an optionally substituted C₃₋₈ cycloalkyl group; morepreferably, an optionally substituted cyclohexyl) or an optionallysubstituted alicyclic heterocyclic ring group (preferably, an optionallysubstituted saturated alicyclic heterocyclic ring group (preferably6-membered ring group); more preferably, an optionally substitutedtetrahydropyranyl, an optionally substituted tetrahydrothiopyranyl or anoptionally substituted piperidyl; most preferably, an optionallysubstituted tetrahydropyranyl) is preferable.Among them, a compound of the formula:

wherein X^(ea−) is an anion is preferable.

In the above formula, examples of the anion represented by X^(ea−)include an anion of a halogen atom; an anion derived from an inorganicacid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuricacid, phosphoric acid, etc.; an anion derived from an organic acid suchas formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalicacid, tartaric acid, maleic acid, citric acid, succinic acid, malicacid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonicacid, etc.; an anion derived from an acidic amino acid such as asparticacid, glutamic acid, etc.; etc. Among them, an anion of a halogen atomis preferable.

In the above formula (eIb), the substituents of “phenyl group” in the“phenyl group which may be substituted” and the substituents of “thienylgroup” in the “thienyl group which may be substituted” shown by R^(e1b)include those mentioned as the substituents in “5- to 6-membered cyclicring group” shown by R^(e1).

In the above formula (eIb), Y^(eb) is —CH₂—, —O— or —S—; and preferably—CH₂— or —O—.

In the above formula (eIb), R^(e2b), R^(e3b) and R^(e4b) areindependently an “optionally substituted aliphatic hydrocarbon group” oran “optionally substituted alicyclic heterocyclic ring group”.

Examples of the “aliphatic hydrocarbon group” in the “optionallysubstituted aliphatic hydrocarbon group” represented by R^(e2b), R^(e3b)and R^(e4b) include

-   (1) an optionally substituted alkyl (e.g. C₁₋₁₀ alkyl such as    methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,    tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl,    nonyl, decyl, etc., preferably C₁₋₆ alkyl, etc.);-   (2) an optionally substituted cycloalkyl (e.g. C₃₋₈ cycloalkyl, etc.    such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    cycloheptyl, cyclooctyl, etc.);-   (3) an optionally substituted alkenyl (e.g. alkenyl which has a    carbon number of 2 to 10 such as allyl, crotyl, 2-pentenyl,    3-hexenyl, etc., preferably alkenyl, etc.);-   (4) an optionally substituted cycloalkenyl (e.g. cycloalkenyl which    has a carbon number 3 to 7, such as 2-cyclopentenyl, 2-cyclohexenyl,    2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.); etc.

Examples of the “alicyclic heterocyclic ring group” in the “optionallysubstituted alicyclic heterocyclic ring group” represented by R^(e2b),R^(e3b) and R^(e4b) include group formed by removing a hydrogen atomfrom a 5- to 6-membered non-aromatic heterocyclic ring containing 1 to 4hetero-atoms consisting of 1 to 2 kinds of hetero-atoms selected fromnitrogen atom, sulfur atom and oxygen atom such as tetrahydrofuran,tetrahydrothiophene, dithiolane, oxathiolane, pyrrolidine, pyrroline,imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine,piperazine, oxazine, oxadiazine, thiazine, thiadiazine, morpholine,thiomorpholine, pyran, tetrahydropyran, etc.; preferably a group formedby removing a hydrogen atom from a 5- to 6-membered saturatedheterocyclic ring, containing 1 hetero-atom such as tetrahydrofuran,piperidine, tetrahydropyran, tetrahydrothiopyran, etc.

Examples of the substituents, which the “aliphatic hydrocarbon group”and the “alicyclic heterocyclic ring group” in the “optionallysubstituted aliphatic hydrocarbon group” and the “optionally substitutedalicyclic heterocyclic ring group” represented by R^(e2b), R^(e3b) andR^(e4b) may have, include halogen (e.g. fluorine, chlorine, bromine,iodine, etc.), an optionally halogenated C₁₋₄ alkyl, an optionallyhalogenated C₁₋₄ alkoxy (e.g. methoxy, ethoxy, trifluoromethoxy,trifluoroethoxy, etc.), C₂₋₄ alkanoyl (e.g. acetyl, propionyl, etc.),C₁₋₄ alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.), phenyl,phenyl C₁₋₄ alkyl, C₃₋₇ cycloalkyl, cyano, nitro, oxo, hydroxy,mercapto, amino, carboxyl, C₁₋₄ alkoxy-carbonyl (preferably, halogen, anoptionally halogenated C₁₋₄ alkyl, an optionally halogenated C₁₋₄alkoxy, phenyl C₁₋₄ alkyl, C₃₋₇ cycloalkyl, cyano, oxo, hydroxy group,etc.), etc., and the number of the substituents are preferably 1 to 3.

In the above formula (eIb), as the group R^(e2b) or R^(e3b), anoptionally substituted chain hydrocarbon group is preferable, and anoptionally substituted alkyl group is more preferable. In particular,the groups R^(e2b) and R^(e3b) are preferably the same and morepreferably both of the groups R^(e2b) and R^(e3b) are methyl.

In the above formula (eIb), as the group R^(e4b), an optionallysubstituted alicyclic hydrocarbon group or an optionally substitutedalicyclic heterocyclic group is preferable and an optionally substitutedcycloalkyl group or an optionally substituted saturated alicyclicheterocyclic ring group is more preferable. In particular, R^(e4b) ispreferably an optionally substituted cyclohexyl or an optionallysubstituted 6-membered saturated alicyclic heterocyclic ring group andmore preferably an optionally substituted cycloalkyl, an optionallysubstituted tetrahydropyranyl, an optionally substitutedtetrahydrothiopyranyl or an optionally substituted piperidyl.

In the formula (eIc), R^(e1) has the same meaning given above.

In the above formula (eIc), the substituent of the 6- to 7-membered ringin a “6- to 7-membered ring which may be substituted” represented byA^(ec) include those which the “5- to 6-membered ring” in the“optionally substituted 5- to 6-membered ring” represented by R^(e1) mayhave. One to three (preferably one to two) of the substituents of A^(ec)are the same or different each other and may be present at any positionon the ring.

In the group of the formula:

a carbon atom at the position ea is preferably unsubstituted.

Examples of the “optionally substituted 6- to 7-membered ring”represented by A^(ec) include a 6- to 7-membered ring group of theformula:

which may have a substituent at any possible position, etc.

In the above formula, Y^(e) has the same meaning given above.

Examples of the “substituents”, which the “benzene ring” in the“optionally substituted benzene ring” represented by B^(ec) may have,include those for the “5- to 6-membered ring” in the “optionallysubstituted 5- to 6-membered ring” represented by R^(e1), etc. Amongthem, halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), nitro,cyano, hydroxy group, an optionally substituted thiol group (e.g. thiol,C₁₋₄ alkylthio, etc.), an optionally substituted amino group (e.g.amino, mono-C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, 5- to 6-membered cyclicamino such as tetrahydropyrrole, piperazine, piperidine, morpholine,thiomorpholine, pyrrole, imidazole, etc., etc.), an optionallyesterified or amidated carboxyl group (e.g. carboxyl, C₁₋₄alkoxy-carbonyl, carbamoyl, mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄alkylcarbamoyl, etc.), an optionally halogenated C₁₋₄ alkyl (e.g.trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C₁₋₄alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,trifluoroethoxy, etc.), formyl, C₂₋₄ alkanoyl (e.g. acetyl, propionyl,etc.), C₁₋₄ alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.),etc. are preferable and in particular, halogen, an optionallyhalogenated C₁₋₄ alkyl, an optionally halogenated C₁₋₄ alkoxy, etc. arepreferable. The number of the substituents is preferably 1 to 3.

In the above formula (eIc), n is an integer of 1 or 2 (preferably, 2).

In the above formula (eIc), the divalent group represented by Z^(e2) hasthe same meaning given above.

In the above formula (eIc), examples of (1) an optionally substitutedamino group in which a nitrogen atom may form a quaternary ammonium, (2)an optionally substituted nitrogen-containing heterocyclic ring groupwhich may contain a sulfur atom or an oxygen atom as ring constitutingatoms and wherein a nitrogen atom may form a quaternary ammonium, (3) agroup binding through a sulfur atom and (4) a group of the formula:

wherein each symbols has the same meanings given above, represented byR^(e2c) are the same as those of R^(e2) mentioned above.

In the above formula (eId), examples of the “5- to 6-membered aromaticring” of the “5- to 6-membered aromatic ring which has a group of theformula: R^(ed)-Z^(e1d)—X^(ed)-Z^(e2d)— wherein R^(ed) is a hydrogenatom or an optionally substituted hydrocarbon group, X^(ed) is anoptionally substituted alkylene chain, and Z^(e1d) and Z^(e2d) arerespectively hetero-atoms, include a 6-membered aromatic hydrocarbonsuch as benzene, etc.; 5- to 6-membered aromatic heterocyclic ringcontaining 1 to 4 hetero-atoms consisting of 1 to 2 kinds ofhetero-atoms selected from nitrogen atom, sulfur atom and oxygen atomsuch as furan, thiophene, pyrrole, imidazole, pyrazole, thiazole,oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine,pyrimidine, pyridazine, triazole, etc.; etc. Among them, benzene, furan,thiophene, pyridine, etc. are preferable, benzene, furan or thiophene ismore preferable, and in particular, benzene is preferable.

Examples of the “hydrocarbon group” in the “optionally substitutedhydrocarbon group” represented by R^(ed) include

-   (1) alkyl (e.g. C₁₋₁₀ alkyl such as methyl, ethyl, propyl,    isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,    isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.,    preferably lower (C₁₋₆) alkyl, etc., more preferably lower (C₁₋₄)    alkyl, etc.);-   (2) cycloalkyl (e.g. C₃₋₇ cycloalkyl, etc. such as cyclopropyl,    cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.);-   (3) alkenyl (e.g. alkenyl which has a carbon number of 2 to 10 such    as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., preferably lower    (C₂₋₆) alkenyl, etc.);-   (4) cycloalkenyl (e.g. cycloalkenyl which has a carbon number of 3    to 7, etc. such as 2-cyclopentenyl, 2-cyclohexenyl,    2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.);-   (5) alkynyl (e.g. alkynyl which has a carbon number of 2 to 10 such    as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-pentynyl,    3-hexynyl, etc., preferably lower (C₂₋₆) alkynyl, etc.);-   (6) aralkyl (e.g. phenyl-C₁₋₄ alkyl (e.g. benzyl, phenethyl, etc.),    etc.);-   (7) aryl (e.g. phenyl, naphthyl, etc.);-   (8) cycloalkyl-alkyl (e.g. C₃₋₇ cycloalkyl-C₁₋₄ alkyl such as    cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,    cyclohexylmethyl, cycloheptylmethyl), etc.

Examples of the substituents, which the above-mentioned (1) alkyl, (2)cycloalkyl, (3) alkenyl, (4) cycloalkenyl, (5) alkynyl, (6) aralkyl, (7)aryl and (8) cycloalkyl-alkyl may have, include halogen (e.g. fluorine,chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, anoptionally substituted thiol group (e.g., thiol, C₁₋₄ alkylthio, etc.),an optionally substituted amino group (e.g., amino, mono-C₁₋₄alkylamino, di-C₁₋₄ alkylamino, 5- to 6-membered cyclic amino such astetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine,pyrrole, imidazole, etc., etc.), an optionally esterified or amidatedcarboxyl group (e.g. carboxyl, C₁₋₄ alkoxy-carbonyl, carbamoyl,mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄ alkylcarbamoyl, etc.), an optionallyhalogenated C₁₋₄ alkyl (e.g. trifluoromethyl, methyl, ethyl, etc.), anoptionally halogenated C₁₋₄ alkoxy (e.g. methoxy, ethoxy, propoxy,butoxy, trifluoromethoxy, trifluoroethoxy, etc.), C₁₋₄ alkylenedioxy(e.g. —O—CH₂—O—, —O—CH₂—CH₂—O—, etc.), an optionally substitutedsulfonamide [a group formed by combining an optionally substituted aminogroup (e.g. amino, a mono-C₁₋₄ alkyklamino, di-C₁₋₄ alkylamino, 5- to6-membered cyclic amino such as tetrahydropyrrole, piperazine,piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.) with—SO₂—, etc.], formyl, C₂₋₄ alkanoyl (e.g. acetyl, propionyl, etc.), C₁₋₄alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.), anoptionally substituted heterocyclic group etc., and the number of thesubstituents are preferably 1 to 3.

The “heterocyclic group” in the “optionally substituted heterocyclicgroup” which is the substituent for the “optionally substitutedhydrocarbon group” represented by R^(ed) is exemplified by a group whichis formed by removing one hydrogen atom from an aromatic heterocyclicring or non-aromatic heterocyclic ring. The aromatic heterocyclic ringinclude a 5- to 6-membered aromatic heterocyclic ring, which contains 1to 4 hetero atoms of 1 to 2 kinds selected from the nitrogen atom, thesulfur atom and the oxygen atom, such as furan, thiophene, pyrrole,imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole,tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole,oxadiazole, thiadiazole or the like, and the non-aromatic heterocyclicring includes a 5- to 6-membered non-aromatic heterocyclic ring, whichcontains 1 to 4 heteroatoms of 1 to 2 kinds selected from the nitrogenatom, the sulfur atom and the oxygen atom, such as tetrahydrofuran,tetrahydrothiophene, dioxolan dithiolan, oxathiolan, pyrrolidine,pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline,piperidine, piperazine, oxazine, oxadiazine, thiazine, thiadiazine,morpholine, thiomorpholine, pyran, tetrahydropyran or the like andnon-aromatic heterocyclic ring group formed by being saturated all or apart of the bond of the ring (preferably, aromatic heterocyclic ringsuch as pyrazole, thiazole, oxazole tetrazole or the like).

Examples of “heterocyclic ring” of “heterocyclic group that may besubstituted” which is the substituent of the “optionally substitutedhydrocarbon group” represented by R^(ed), may optionally have 1 to 3substituents at any substitutable position. The substituent include ahalogen atom (e.g. fluorine, chlorine, bromine, iodine, et.), nitro,cyano, hydroxyl, a thiol group which may be substituted (e.g. thiol, aC₁₋₄ alkylthio, etc.), an amino group which may be substituted (e.g.amino, a mono-C₁₋₄ alkylamino, a di-C₁₋₄ alkylamino, a 5- to 6-memberedcyclic amino such as tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole, imidazole, etc.), an optionallyesterified or amidated carboxyl group (e.g. carboxyl, C₁₋₄alkoxy-carbonyl, carbamoyl, mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄alkylcarbamoyl, etc.), an optionally halogenated C₁₋₄ alkyl (e.g.trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C₁₋₄alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,trifluoroethoxy, etc.), C₁₋₄ alkylenedioxy (e.g. —O—CH₂—O—,—O—CH₂—CH₂—O—, etc.), an optionally substituted sulfonamide [a groupformed by combining an optionally substituted amino group (e.g. amino, amonoC₁₋₄ alkyklamino, diC₁₋₄ alkylamino, 5- to 6-membered cyclic aminosuch as tetrahydropyrrole, piperazine, piperidine, morpholine,thiomorpholine, pyrrole, imidazole, etc.) with —SO₂—, etc.], formyl,C₂₋₄ alkanoyl (e.g. acetyl, propionyl, etc.), C₁₋₄ alkylsulfonyl (e.g.methanesulfonyl, ethanesulfonyl, etc.), (preferably C₁₋₄ alkyl etc.).

When the group of the formula: R^(ed)-Z^(e1d)—X^(ed)-Z^(e2d)— (whereineach symbol has the same meaning given above) is a monovalent group, itdoes not bind to the 5- to 6-membered aromatic ring to form a ring, anoptionally substituted alkyl group is preferable as the group R^(ed), anoptionally halogenated lower alkyl group is more preferable, and inparticular, an optionally halogenated C₁₋₄ alkyl group is preferable.

In the above formula (eId), examples of the “optionally substitutedalkylene chain” represented by X^(ed) include an optionally substitutedstraight or branched C₁₋₆ alkylene, etc. In the alkylene chain, astraight portion is preferably formed by 1-4 carbon atoms, and inparticular, an optionally substituted straight C₁₋₄ alkylene (preferablyethylene or propylene) is preferable as X^(ed).

Examples of the substituent, which the “alkylene chain” in the“optionally substituted alkylene chain” represented by X^(ed) may have,include any one of which can bind to a divalent chain constituting thestraight portion, for example, lower alkyl which has a carbon number of1 to 6 (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.), lower(C₃₋₇) cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, etc.), formyl, lower (C₂₋₇) alkanoyl (e.g.acetyl, propionyl, butyryl, etc.), an optionally esterified phosphonogroup, an optionally esterified carboxyl group, hydroxy group, oxo,etc., and more preferably lower alkyl which has a carbon number of 1 to6 (preferably C₁₋₃ alkyl), hydroxy group, oxo, etc.

Examples of the optionally esterified phosphono group include a group ofthe formula: P(O) (OR^(e7d)) (OR^(e8d)) wherein R^(e7d) and R^(e8d) areindependently hydrogen, a alkyl group which has a carbon number of 1 to6 or a cycloalkyl group which has a carbon number of 3 to 7, and R^(e7d)and R^(e8d) may bind to each other to form a 5- to 7-membered ring.

In the above formula, examples of the alkyl group which has a carbonnumber of 1 to 6 represented by R^(e7d) and R^(e8d) include methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, hexyl, etc., and examples of thecycloalkyl which has a carbon number of 3 to 7 include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. Among them, astraight-chain lower alkyl which has a carbon number of 1 to 6 ispreferable and lower alkyl which has a carbon number of 1 to 3 is morepreferable. The groups R^(e7d) and R^(e8d) may be same or different, andpreferably the groups R^(e7d) and R^(e8d) are same. When R^(e7d) andR^(e8d) may bind to each other to form a 5- to 7-membered ring, thegroups R^(e7d) and R^(e8d) bind to each other to represent astraight-chain C₂₋₄ alkylene side chain of the formula: —(CH₂)₂—,—(CH₂)₃—, —(CH₂)₄—, etc. The side chain may have a substituent, andexamples of the substituent include hydroxy group, halogen, etc.

Examples of the optionally esterified carboxyl group include an estergroup formed by binding a carboxyl group to an alkyl group which has acarbon number of 1 to 6 or a cycloalkyl group which has a carbon numberof 3 to 7 (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, tert-butoxy-carbonyl, pentyloxycarbonyl,hexyloxycarbonyl, etc.).

As the group X^(ed), an optionally substituted C₁₋₄ alkylene ispreferable, C₁₋₄ alkylene which may be substituted with C₁₋₃ alkyl,hydroxy group or oxo is more preferable, and in particular, a group ofthe formula: —(CH₂)_(en)— (en is an integer of 1-4) is preferable.

Examples of the hetero-atom represented by Z^(e1d) and Z^(e2d) include—O—, —S(O)_(em)— (em is an integer of 0 to 2), —N(R^(e4d))— (R^(e4d) isa hydrogen atom or an optionally substituted lower alkyl group), etc. Asthe group Z^(e1d), —O_or —S(O)_(em)— (em is an integer of 0 to 2) ispreferable, and —O— is more preferable. As the group Z^(e2d), —O— or—N(R^(e4d))— (R^(e4d) is a hydrogen atom or an optionally substitutedlower alkyl group) is preferable, and —O— is more preferable.

Examples of the “optionally substituted lower alkyl group” representedby R^(e4d) are similar to the above “optionally substituted lower alkylgroup” exemplified in the “optionally substituted hydrocarbon group”represented by R^(ed).

Examples of the further substituent, which the “5- to 6-membered ring”in the “5- to 6-membered aromatic ring which has a group of the formula:R^(ed)-Z^(e1d)—X^(ed)-Z^(e2d)— wherein each symbol is the same meaninggiven above, and which may have a further substituent” represented byR^(e1d) may have, in addition to the group of the formula:R^(ed)-Z^(e1d)—X^(ed)-Z^(e2d)—, include a halogen atom, nitro, cyano, anoptionally substituted alkyl, an optionally substituted cycloalkyl, anoptionally substituted hydroxy group, an optionally substituted thiolgroup (wherein a sulfur atom may be oxidized to form an optionallysubstituted sulfinyl group or an optionally substituted sulfonyl group),an optionally substituted amino group, an optionally substituted acylgroup, an optionally esterified or amidated carboxyl group, anoptionally substituted aromatic group.

Examples of the halogen as the substituents for R^(e1d) includefluorine, chlorine, bromine, iodine, etc. Among them, fluorine andchlorine are preferable.

Examples of the alkyl in the optionally substituted alkyl as thesubstituents for R^(e1d) include a straight or branched alkyl that has acarbon number of 1 to 10 such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,hexyl, heptyl, octyl, nonyl, decyl, etc., and preferably lower (C₁₋₆)alkyl.

Examples of the substituents in the optionally substituted alkyl includehalogen (e.g. fluorine, chlorine, bromine, iodine, etc.), nitro, cyano,hydroxy group, an optionally substituted thiol group (e.g. thiol, C₁₋₄alkylthio, etc.), an optionally substituted amino group (e.g. amino,mono-C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, 5- to 6-membered cyclic aminosuch as tetrahydropyrrole, piperazine, piperidine, morpholine,thiomorpholine, pyrrole, imidazole, etc., etc.), an optionallyesterified or amidated carboxyl group (e.g. carboxyl, C₁₋₄alkoxy-carbonyl, carbamoyl, mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄alkylcarbamoyl, etc.), an optionally halogenated C₁₋₄ alkoxy (e.g.methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy,etc.), an optionally halogenated C₁₋₄ alkoxy-C₁₋₄ alkoxy (e.g.methoxymethoxy, methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy,trifluoroethoxyethoxy, etc.), formyl, C₂₋₄ alkanoyl (e.g. acetyl,propionyl, etc.), C₁₋₄ alkylsulfonyl (e.g. methanesulfonyl,ethanesulfonyl, etc.), etc., and the number of the substituents arepreferably 1 to 3.

Examples of the cycloalkyl in the optionally substituted cycloalkyl asthe substituents for R^(e1d) include C₃₋₇ cycloalkyl, etc. such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.

Examples of the substituents in the optionally substituted cycloalkylinclude halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), nitro,cyano, hydroxy group, an optionally substituted thiol group (e.g. thiol,C₁₋₄ alkylthio, etc.), an optionally substituted amino group (e.g.amino, mono-C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, 5- to 6-membered cyclicamino such as tetrahydropyrrole, piperazine, piperidine, morpholine,thiomorpholine, pyrrole, imidazole, etc., etc.), an optionallyesterified or amidated carboxyl group (e.g. carboxyl, C₁₋₄alkoxy-carbonyl, carbamoyl, mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄alkylcarbamoyl, etc.), an optionally halogenated C₁₋₄ alkyl (e.g.trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C₁₋₄alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,trifluoroethoxy, etc.), formyl, C₂₋₄ alkanoyl (e.g. acetyl, propionyl,etc.), C₁₋₄ alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.),etc., and the number of the substituents are preferably 1 to 3.

Examples of the substituents in the optionally substituted hydroxy groupas the substituents for. Red include:

-   (1) an optionally substituted alkyl (e.g. C-₁₋₁₀ alkyl such as    methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,    tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl,    nonyl, decyl, etc., preferably lower (C₁₋₆) alkyl, etc.);-   (2) an optionally substituted cycloalkyl which may contain a    hetero-atom (e.g. C₃₋₇ cycloalkyl such as cyclopropyl, cyclobutyl,    cyclopentyl, cyclohexyl, cycloheptyl, etc.; a saturated 5- to    6-membered heterocyclic ring group containing 1 to 2 hetero-atoms    such as tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl,    pyrazolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl,    tetrahydropyranyl, tetrahydrothiopyranyl, etc (preferably,    tetrahydropyranyl, etc.); etc.);-   (3) an optionally substituted alkenyl (e.g. alkenyl which has a    carbon number of 2 to 10 such as allyl, crotyl, 2-pentenyl,    3-hexenyl, etc., preferably lower (C₂₋₆)alkenyl, etc.);-   (4) an optionally substituted cycloalkenyl (e.g. cycloalkenyl which    has a carbon number of 3 to 7, etc. such as 2-cyclopentenyl,    2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.);-   (5) an optionally substituted aralkyl (e.g. phenyl-C₁₋₄ alkyl (e.g.    benzyl, phenethyl, etc.), etc.);-   (6) formyl or an optionally substituted acyl (e.g. alkanoyl which    has a carbon number of 2 to 4 (e.g. acetyl, propionyl, butyryl,    isobutyryl, etc.), alkylsulfonyl which has a carbon number of 1 to 4    (e.g. methanesulfonyl, ethanesulfonyl, etc.), etc.);-   (7) an optionally substituted aryl (e.g. phenyl, naphthyl, etc.);    etc.

Examples of the substituents which the above-mentioned (1) optionallysubstituted alkyl, (2) optionally substituted cycloalkyl, (3) optionallysubstituted alkenyl, (4) optionally substituted cycloalkenyl, (5)optionally substituted aralkyl, (6) optionally substituted acyl and (7)optionally substituted aryl may have include halogen (e.g., fluorine,chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, anoptionally substituted thiol group (e.g., thiol, C₁₋₄ alkylthio, etc.),an optionally substituted amino group (e.g. amino, mono-C₁₋₄ alkylamino,di-C₁₋₄ alkylamino, 5- to 6-membered cyclic amino such astetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine,pyrrole, imidazole, etc., etc.), an optionally esterified or amidatedcarboxyl group (e.g. carboxyl, C₁₋₄ alkoxy-carbonyl, carbamoyl,mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄ alkylcarbamoyl, etc.), an optionallyhalogenated C₁₋₄ alkyl (e.g. trifluoromethyl, methyl, ethyl, etc.), anoptionally halogenated C₁₋₆ alkoxy (e.g. methoxy, ethoxy, propoxy,butoxy, trifluoromethoxy, trifluoroethoxy, etc.; preferably anoptionally halogenated C₁₋₄ alkoxy), formyl, C₂₋₄ alkanoyl (e.g. acetyl,propionyl, etc.), C₁₋₄ alkylsulfonyl (e.g. methanesulfonyl,ethanesulfonyl, etc.), an optionally substituted 5- to 6-memberedaromatic heterocyclic ring [e.g. 5- to 6-membered aromatic heterocyclicring containing 1 to 4 hetero-atoms consisting of 1 to 2 kinds ofhetero-atoms selected from nitrogen atom, sulfur atom and oxygen atomsuch as furan, thiophene, pyrrole, imidazole, pyrazole, thiazole,oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine,pyrimidine, pyridazine, triazole, etc.; Examples of the substituentswhich the heterocyclic ring may have include halogen (e.g. fluorine,chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, thiolgroup, amino group, carboxyl group, an optionally halogenated C₁₋₄ alkyl(e.g. trifluoromethyl, methyl, ethyl, etc.), an optionally halogenatedC₁₋₄ alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,trifluoroethoxy, etc.), formyl, C₂₋₄ alkanoyl (e.g. acetyl, propionyl,etc.), C₁₋₄ alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.),etc., and the number of the substituents are preferably 1 to 3], etc.,and the number of the substituents are preferably 1 to 3.

Examples of the substituents in the optionally substituted thiol groupas the substituents for R^(e1d) are similar to the above-describedsubstituents in the optionally substituted hydroxy group as thesubstituents for R^(e1d), and among them,

-   (1) an optionally substituted alkyl (e.g. C₁₋₁₀ alkyl such as    methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,    tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl,    nonyl, decyl, etc., preferably lower (C₁₋₆) alkyl, etc.);-   (2) an optionally substituted cycloalkyl (e.g. C₃₋₇ cycloalkyl, etc.    such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    cycloheptyl, etc.);-   (3) an optionally substituted aralkyl (e.g. phenyl-C₁₋₄ alkyl (e.g.    benzyl, phenethyl, etc.), etc.);-   (4) an optionally substituted aryl (e.g. phenyl, naphthyl, etc.);    etc. are preferable.

Examples of the substituents which the above-mentioned (1) optionallysubstituted alkyl, (2) optionally substituted cycloalkyl, (3) optionallysubstituted aralkyl and (4) optionally substituted aryl may have includehalogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano,hydroxy group, an optionally substituted thiol group (e.g., thio, C₁₋₄alkylthio, etc.), an optionally substituted amino group (e.g. amino,mono-C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, 5- to 6-membered cyclic aminosuch as tetrahydropyrrole, piperazine, piperidine, morpholine,thiomorpholine, pyrrole, imidazole, etc., etc.), an optionallyesterified or amidated carboxyl group (e.g. carboxyl, C₁₋₄alkoxy-carbonyl, carbamoyl, mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄alkylcarbamoyl, etc.), an optionally halogenated C₁₋₄ alkyl (e.g.trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C₁₋₄alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,trifluoroethoxy, etc.), formyl, C₂₋₄ alkanoyl (e.g. acetyl, propionyl,etc.), C₁₋₄ alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.),etc., and the number of the substituents are preferably 1 to 3.

Examples of the substituents in the optionally substituted amino groupas the substituents for R^(e1d) include an amino group which may haveone to two substituents similar to the above-described substituents inthe optionally substituted hydroxy group as the substituents forR^(e1d), etc. Among them,

-   (1) an optionally substituted alkyl (e.g. C₁₋₁₀ alkyl such as    methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,    tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl,    nonyl, decyl, etc., preferably lower (C₁₋₆) alkyl, etc.);-   (2) an optionally substituted cycloalkyl (e.g. C₃₋₇ cycloalkyl, etc.    such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    cycloheptyl, etc.);-   (3) an optionally substituted alkenyl (e.g. alkenyl which has a    carbon number of 2 to 10 such as allyl, crotyl, 2-pentenyl,    3-hexenyl, etc., preferably lower (C₂₋₆) alkenyl, etc.);-   (4) an optionally substituted cycloalkenyl (e.g. cycloalkenyl which    has a carbon number of 3 to 7, etc. such as 2-cyclopentenyl,    2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.);-   (5) formyl or an optionally substituted acyl (e.g. alkanoyl which    has a carbon number of 2 to 4 (e.g. acetyl, propionyl, butyryl,    isobutyryl, etc.), which has a carbon number of 1 to 4 alkylsulfonyl    (e.g. methanesulfonyl, ethanesulfonyl, etc.), etc.);-   (6) an optionally substituted aryl (e.g. phenyl, naphthyl, etc.);    etc. are preferable.

Examples of the substituents, which each of the above-described (1)optionally substituted alkyl, (2) optionally substituted cycloalkyl, (3)optionally substituted alkenyl, (4) optionally substituted cycloalkenyl,(5) optionally substituted acyl and (6) optionally substituted aryl mayhave, include halogen (e.g. fluorine, chlorine, bromine, iodine, etc.),nitro, cyano, hydroxy group, an optionally substituted thiol group (e.g.thiol, C₁₋₄ alkylthio, etc.), an optionally substituted amino group(e.g. amino, mono-C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, 5- to 6-memberedcyclic amino such as tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole, imidazole, etc., etc.), anoptionally esterified or amidated carboxyl group (e.g. carboxyl, C₁₋₄alkoxy-carbonyl, carbamoyl, mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄alkylcarbamoyl, etc.), an optionally halogenated C₁₋₄ alkyl (e.g.trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C₁₋₄alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,trifluoroethoxy, etc.), formyl, C₂₋₄ alkanoyl (e.g. acetyl, propionyl,etc.), C₁₋₄ alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.),etc., and the number of the substituents is preferably 1 to 3.

The substituents in the optionally substituted amino group as thesubstituents for R^(e1d) may bind to each other to form a cyclic aminogroup (e.g. 5- to 6-membered cyclic amino, etc. such astetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine,pyrrole, imidazole, etc.). The cyclic amino group may have asubstituent, and examples of the substituents include halogen (e.g.fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group,an optionally substituted thiol group (e.g. thiol, C₁₋₄ alkylthio,etc.), an optionally substituted amino group (e.g. amino, mono-C₁₋₄alkylamino, di-C₁₋₄ alkylamino, 5- to 6-membered cyclic amino such astetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine,pyrrole, imidazole, etc., etc.), an optionally esterified or amidatedcarboxyl group (e.g. carboxyl, C₁₋₄ alkoxy-carbonyl, carbamoyl,mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄ alkylcarbamoyl, etc.), an optionallyhalogenated C₁₋₄ alkyl (e.g. trifluoromethyl, methyl, ethyl, etc.), anoptionally halogenated C₁₋₄ alkoxy (e.g. methoxy, ethoxy, propoxy,butoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, C₂₋₄ alkanoyl(e.g. acetyl, propionyl, etc.), C₁₋₄ alkylsulfonyl (e.g.methanesulfonyl, ethanesulfonyl, etc.), etc., and the number of thesubstituents is preferably 1 to 3.

Examples of the optionally substituted acyl as the substituents forR^(e1d) include a carbonyl group or a sulfonyl group binding to

-   (1) hydrogen;-   (2) an optionally substituted alkyl (e.g. C₁₋₁₀ alkyl such as    methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,    tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl,    nonyl, decyl, etc., preferably lower (C₁₋₆) alkyl, etc.);-   (3) an optionally substituted cycloalkyl (e.g. C₃₋₇ cycloalkyl, etc.    such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    cycloheptyl, etc.);-   (4) an optionally substituted alkenyl (e.g. alkenyl which has a    carbon number of 2 to 10 such as allyl, crotyl, 2-pentenyl,    3-hexenyl, etc., preferably lower (C₂₋₆) alkenyl, etc.);-   (5) an optionally substituted cycloalkenyl (e.g. cycloalkenyl which    has a carbon number of 3 to 7, etc. such as 2-cyclopentenyl,    2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.);-   (6) an optionally substituted 5- to 6-membered monocyclic aromatic    group (e.g. phenyl, etc., 5- to 6-membeed aromatic heterocyclic    group containing 1 to 4 hetero-atoms of 1 to 2 kinds selected from    nitrogen atom, sulfur atom and oxygen atom, such as furyl, thienyl,    pyrrolyl, imidazole, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl,    isoxazolyl, tetrazolyl, pyridyl, pyrazyl, pyrimidyl, pyridazinyl,    triazolyl, etc., preferably, pyridyl, thienyl, etc.)-   (7) an optionally substituted 5- to 6-membered monocyclic    non-aromatic heterocyclic group (a group formed by removing one    hydrogen atom from a 5- to 6-membered monocyclic non-aromatic    heterocyclic ring which contains 1 to 4 heteroatoms of 1 to 2 kinds    selected from nitrogen atom, sulfur atom and oxygen atom such as    tetrahydrofuran, tetrahydrothiophene, dithiolane, oxathiolane,    pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine,    pyrazoline, piperidine, piperazine, oxazine, oxadiazine, thiazine,    thiadiazine, morpholine, thiomorpholine, pyran, tetrahydropyran,    etc., preferably dioxolanyl, etc.) with carbonyl or sulfonyl group    (e.g. acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl,    pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl,    cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl,    crotonyl, 2-cyclohexenecarbonyl, benzoyl, nicotinoyl,    methanesulfonyl, ethanesulfonyl, etc.).

Examples of the substituents, which the above-mentioned (2) optionallysubstituted alkyl, (3) optionally substituted cycloalkyl, (4) optionallysubstituted alkenyl, (5) optionally substituted cycloalkenyl, (6)optionally substituted 5- to 6-membered monocyclic aromatic group and(7) optionally substituted 5- to 6-membered non-aromatic heterocyclicgroup may have, include a halogen (e.g. fluorine, chlorine, bromine,iodine, etc.), nitro, cyano, hydroxyl group, an optionally substitutedthiol group (e.g. thiol, C₁₋₄ alkylthio, etc.), an optionallysubstituted amino group (e.g. amino, mono-C₁₋₄ alkylamino, di-C₁₋₄alkylamino, a 5- to 6-membered cyclic amino such as tetrahydropyrrole,piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole,etc., etc.), an optionally esterified or amidated carboxyl group (e.g.carboxyl, C₁₋₄ alkoxy-carbonyl, carbamoyl, mono-C₁₋₄ alkylcarbamoyl,di-C₁₋₄ alkylcarbamoyl, etc.), an optionally halogenated C₁₋₄ alkyl(e.g. trifluoromethyl, methyl, ethyl, etc.), an optionally halogenatedC₁₋₄ alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,trifluoroethoxy, etc.), C₁₋₄ alkylenedioxy (e.g. —O—CH₂—O—,—O—CH₂—CH₂—O—, etc.), an optionally substituted sulfonamide [a groupformed by combining an optionally substituted amino group (e.g. amino, amonoC₁₋₄ alkyklamino, diC₁₋₄ alkylamino, 5- to 6-membered cyclic aminosuch as tetrahydropyrrole, piperazine, piperidine, morpholine,thiomorpholine, pyrrole, imidazole, etc.) with —SO₂—, etc.], formyl, aC₂₋₄ alkanoyl (e.g. acetyl, propionyl, etc.), C₁₋₄ alkylsulfonyl (e.g.methanesulfonyl, ethanesulfonyl, etc.), etc., and the number of thesubstituents are preferably 1 to 3.

Examples of the optionally esterified carboxyl group as the substituentsfor R^(e1d) include a carbonyloxy group binding to

-   (1) hydrogen;-   (2) an optionally substituted alkyl (e.g. C₁₋₁₀ alkyl such as    methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,    tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl,    nonyl, decyl, etc., preferably lower (C₁₋₆) alkyl, etc.);-   (3) an optionally substituted cycloalkyl (e.g. C₃₋₇ cycloalkyl, etc.    such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    cycloheptyl, etc.);-   (4) an optionally substituted alkenyl (e.g. alkenyl which has a    carbon number of 2 to 10 such as allyl, crotyl,    2-pentenyl,3-hexenyl, etc., preferably lower (C₂₋₆) alkenyl, etc.);-   (5) an optionally substituted cycloalkenyl (e.g. cycloalkenyl which    has a carbon number of 2 to 1, etc. such as 2-cyclopentenyl,    2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.);-   (6) an optionally substituted aryl (e.g. phenyl, naphthyl, etc.);    etc., and preferably carboxyl, lower (C₁₋₆) alkoxycarbonyl,    aryloxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl,    propoxycarbonyl, phenoxycarbonyl, naphthoxycarbonyl, etc.), etc.

Examples of the substituents, which the above-mentioned (2) optionallysubstituted alkyl, (3) optionally substituted cycloalkyl, (4) optionallysubstituted alkenyl, (5) optionally substituted cycloalkenyl and (6)optionally substituted aryl may have, include halogen (e.g. fluorine,chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, anoptionally substituted thiol group (e.g. thiol, C₁₋₄ alkylthio, etc.),an optionally substituted amino group (e.g. amino, mono-C₁₋₄ alkylamino,di-C₁₋₄ alkylamino, 5- to 6-membered cyclic amino such astetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine,pyrrole, imidazole, etc., etc.), an optionally esterified or amidatedcarboxyl group (e.g. carboxyl, C₁₋₄ alkoxy-carbonyl, carbamoyl,mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄ alkylcarbamoyl, etc.), an optionallyhalogenated C₁₋₄ alkyl (e.g. trifluoromethyl, methyl, ethyl, etc.), anoptionally halogenated C₁₋₄ alkoxy (e.g. methoxy, ethoxy, propoxy,butoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, C₂₋₄ alkanoyl(e.g. acetyl, propionyl, etc.), C₁₋₄ alkylsulfonyl (e.g.methanesulfonyl, ethanesulfonyl, etc.), etc., and the number of thesubstituents are preferably 1 to 3.

Examples of the optionally amidated carboxyl group as the substituentsfor R^(e1d) include an carbonyl group binding to an optionallysubstituted amino group, etc. which is similar to the above-described“optionally substituted amino group as the substituents for R^(e1d)”,and among others, carbamoyl, mono-C₁₋₆ alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, etc. are preferable.

Examples of the aromatic group in the optionally substituted aromaticgroup as the substituents for R^(e1d) include 5- to 6-membered aromatichomocyclic or heterocyclic ring such as phenyl, pyridyl, furyl, thienyl,pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl,isoxazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl,oxadiazolyl, thiadiazolyl, etc.; fused aromatic heterocyclic ring suchas benzofuran, indole, benzothiophene, benzoxazole, benzothiazole,indazole, benzimidazole, quinoline, isoquinoline, quinoxaline,phthalazine, quinazoline, cinnoline, etc.; etc.

Examples of the substituents for these aromatic groups include halogen(e.g. fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxygroup, an optionally substituted thiol group (e.g. thiol, C₁₋₄alkylthio, etc.), an optionally substituted amino group (e.g. amino,mono-C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, 5- to 6-membered cyclic aminosuch as tetrahydropyrrole, piperazine, piperidine, morpholine,thiomorpholine, pyrrole, imidazole, etc., etc.), an optionallyesterified or amidated carboxyl group (e.g. carboxyl, C₁₋₄alkoxy-carbonyl, carbamoyl, mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄alkylcarbamoyl, etc.), an optionally halogenated C₁₋₄ alkyl (e.g.trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C₁₋₄alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,trifluoroethoxy, etc.), formyl, C₂₋₄ alkanoyl (e.g. acetyl, propionyl,etc.), C₁₋₄ alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.),etc., and the number of the substituents is preferably 1 to 3.

The number of the above-mentioned substituents for R^(e1d) is 1-4(preferably 1 to 2) and they may be same or different and present at anypossible position on the ring.

When the group represented by R^(ed) binds to the 5 to 6 memberedaromatic ring to form a ring, the group of the formula:R^(ed)-Z^(e1d)—X^(ed)-Z^(e2d)— wherein each symbol is as defined above(as the group R^(ed) is preferably a hydrogen atom) forms a divalentgroup such as lower (C₁₋₆) alkylenedioxy (e.g., —O—CH₂—O—,—O—CH₂—CH₂—O—, —O—CH₂—CH₂—CH₂—O—, etc.), oxy-lower (C₁₋₆) alkylene-amino(e.g., —O—CH₂—NH—, —O—CH₂—CH₂—NH—, etc.), oxy-lower (C₁₋₆) alkylenethio(e.g., —O—CH₂—S—, —O—CH₂—CH₂—S—, etc.), lower (C₁₋₆) alkylene-diamino(e.g., —NH—CH₂—NH—, —NH—CH₂—CH₂—NH—, etc.), thia-lower (C₁₋₆)alkylene-amino (e.g., —S—CH₂—NH—, —S—CH₂—CH₂—NH—, etc.), etc. Examplesof the further substituent, which the “5 to 6 membered ring”in the “5 to6 membered aromatic ring which has a group of the formula:R^(ed)-Z^(e1d)—X^(ed)-Z^(e2d)— wherein each symbol is as defined above,and which may have a further substituent” represented by R^(e1d) mayhave, in addition to the group of the formula:R^(ed)-Z^(e1d)—X^(ed)-Z^(e2d)—, include a lower (C₁₋₄) alkyl optionallysubstituted with a halogen or a lower (C₁₋₄) alkoxy (e.g. methyl, ethyl,t-butyl, trifluoromethyl, methoxymethyl, ethoxymethyl, propoxymethyl,butoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, butoxyethyl,etc.), a lower (C₁₋₄) alkoxy optionally substituted with a halogen or alower (C₁₋₄) alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, t-butoxy,trifluoromethoxy, methoxymethoxy, ethoxymethoxy, propoxymethoxy,butoxymethoxy, methoxyethoxy, ethoxyethoxy, propoxyethoxy, butoxyethoxy,methoxypropoxy, ethoxypropoxy, propoxypropoxy, butoxypropoxy, etc.),halogen (e.g. fluorine, chlorine, etc.), nitro, cyano, an aminooptionally substituted with 1-2 lower (C₁₋₄) alkyl, formyl or lower(C₂₋₄) alkanoyl (e.g. amino, methylamino, dimethylamino, formylamino,acetylamino, etc.), 5- to 6-membered cyclic amino (e.g. 1-pyrrolidinyl,1-piperazinyl, 1-piperidinyl, 4-morpholino, 4-thiomorpholino,1-imidazolyl, 4-tetrahydropyranyl, etc.), etc.

When R^(e1d) is a benzene, the “group of the formula:R^(ed)-Z^(e1d)—X^(ed)-Z^(e2d)—” is preferably present at para positionand the further substituent, which the “5 to 6 membered aromatic ringwhich may have, in addition to the group of the formula:R^(ed)-Z^(e1d)—X^(ed)-Z^(e2d)—, is preferably present at meta position.

In the above formula, examples of the “optionally substituted iminogroup” represented by Y^(ed) include a divalent group of the formula:—N(R^(e5d))— wherein R^(e5d) is a hydrogen atom or a substituent, etc.

As R^(e5d), a hydrogen atom, an optionally substituted hydrocarbongroup, an optionally substituted heterocyclic group, an optionallysubstituted hydroxyl group, an optionally substituted thiol group (whichmay be oxidized, and form an optionally substituted sulfinyl group or anoptionally substituted sulfonyl group), an optionally substituted aminogroup, an optionally esterified or amidated carboxyl group, and anoptionally substituted acyl group etc., are preferable, and a hydrogenatom, an optionally substituted hydrocarbon group, an optionallysubstituted heterocyclic group, an optionally substituted acyl group,etc. are more preferable. Preferable examples of R^(e5d) include ahydrogen atom, an optionally substituted hydrocarbon group, anoptionally substituted acyl group, etc., and C₁₋₄ alkyl, C₁₋₄alkylsulfonyl, formyl, C₂₋₅ alkanoyl, etc. are more preferable, C₁₋₄alkyl, formyl, C₂₋₅ alkanoyl, etc. are further more preferable, and inparticular, formyl or ethyl is preferable. As examples of preferableembodiment of R^(ed), a group represented by the formula:—(CH₂)_(ek)—R^(e6d), wherein ek is 0 or 1, and R^(e6d) represents anoptionally substituted 5- to 6-membered monocyclic aromatic group (forexample, those similar to “(6) an optionally substituted 5- to6-membered monocyclic aromatic group” mentioned in the item “anoptionally substituted acyl group” as the substitutent of R^(ed) arementioned, and phenyl, pyrazolyl, thiazolyl, oxazolyl, tetrazolyl, eachof which may be substituted by a halogen, an optionally halogenated C₁₋₄alkyl, an optionally halogenated C₁₋₄ alkoxy, etc., etc. arepreferable).

Specific examples of the “optionally substituted hydrocarbon group” asR^(e5d) are similar to the “optionally substituted hydrocarbon group” asR^(ed). Specific examples of the “optionally substituted heterocyclicgroup” as R^(ed) are similar to the “optionally substituted heterocyclicgroup” which is a substituent of the “optionally substituted hydrocarbongroup” represented by R^(ed). Specific examples of the “optionallysubstituted hydroxyl group”, the “optionally substituted thiol group,the “optionally substituted amino group”, the “optionally esterified oramidated carboxyl group” and the “optionally substituted acyl group”,each of which is represented by R^(e5d), are similar to the “optionallysubstituted hydroxyl group”, the “optionally substituted thiol group”,the “optionally substituted amino group”, the “optionally esterified oramidated carboxyl group” and the “optionally substituted acyl group”,each of which is the substituent of R^(e1d), respectively.

In the above formula (eId), examples of the “optionally substitutedaliphatic hydrocarbon group” (aliphatic chain hydrocarbon group andaliphatic cyclic hydrocarbon group) represented by R^(e2d) and R^(e3d)include

-   (1) an optionally substituted alkyl (e.g. C₁₋₁₀ alkyl such as    methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,    tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl,    nonyl, decyl, etc., preferably lower (C₁₋₆) alkyl, etc.);-   (2) an optionally substituted cycloalkyl (e.g. C₃₋₈ cycloalkyl, etc.    such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    cycloheptyl, cyclooctyl, etc.), provided that-   (2-1) the cycloalkyl may contain one hetero-atom selected from a    sulfur atom, an oxygen atom and a nitrogen atom to form oxirane,    thiorane, aziridine, tetrahydrofuran, tetrahydrothiophene,    pyrrolidine, tetrahydropyran, tetrahydrothiopyran,    tetrahydrothiopyran 1-oxide, piperidine, etc. (preferably,    6-membered ring such as tetrahydropyran, tetrahydrothiopyran,    piperidine, etc.); that-   (2-2) the cycloalkyl may be fused with a benzene ring to form    indane, tetrahydronaphthalene, etc. (preferably, indane, etc.); and    that-   (2-3) the cycloalkyl may be clrosslinked via straight-chained, atom    chain having a carbon number of 1 to 2, and may form a crosslinked    cyclic hydrocarbon residue such as bicyclo[2.2.1]heptyl,    bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, etc.,    preferably, a cyclohexyl group, etc. having a bridging comprising a    straight chain formed by 1-2 carbon atoms, and more preferably    bicyclo[2.2.1]heptyl, etc.;-   (3) an optionally substituted alkenyl (e.g. C₂₋₁₀ alkenyl such as    allyl, crotyl, 2-pentenyl,3-hexenyl, etc., preferably lower    (C₂₋₆)alkenyl, etc.);-   (4) an optionally substituted cycloalkenyl (e.g. C₃₋₇ cycloalkenyl,    etc. such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl,    2-cyclohexenylmethyl, etc.); etc.

Examples of the substituents, which the above-mentioned (1) optionallysubstituted alkyl, (2) optionally substituted cycloalkyl, (3) optionallysubstituted alkenyl and (4) optionally substituted cycloalkenyl mayhave, include halogen (e.g. fluorine, chlorine, bromine, iodine, etc.),an optionally halogenated lower (C₁₋₄) alkyl, an optionally halogenatedC₁₋₄ alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,trifluoroethoxy, etc.), C₁₋₄ alkylenedioxy (e.g., —O—CH₂—O—,—O—CH₂—CH₂—O—, etc.), formyl, C₂₋₄ alkanoyl (e.g., acetyl, propionyl,etc.), C₁₋₄ alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.),phenyl-lower (C₁₋₄) alkyl, C₃₋₇ cycloalkyl, cyano, nitro, hydroxy group,an optionally substituted thiol group (e.g. thiol, C₁₋₄ alkylthio,etc.), an optionally substituted amino group (e.g. amino, mono-C₁₋₄alkylamino, di-C₁₋₄ alkylamino, 5- to 6-membered cyclic amino such astetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine,pyrrole, imidazole, etc., etc.), an optionally esterified or amidatedcarboxyl group (e.g. carboxyl, C₁₋₄ alkoxy-carbonyl, carbamoyl,mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄ alkylcarbamoyl, etc.), a lower (C₁₋₄)alkoxy-carbonyl, oxo group (preferably, halogen, an optionallyhalogenated lower (C₁₋₄) alkyl, an optionally halogenated lower (C₁₋₄)alkoxy, phenyl-lower (C₁₋₄) alkyl, C₃₋₇ cycloalkyl, cyano, hydroxygroup, etc.), etc., and the number of the substituents are preferably 1to 3.

Examples of the “optionally substituted aliphatic hydrocarbon group”represented by R^(e2d) and R^(e3d) include

-   (1) a lower (C₁₋₆) straight or branched alkyl which may have 1-3    substituents selected from the class consisting of halogen, cyano,    hydroxy group and C₃₋₇ cycloalkyl;-   (2) C₅₋₈ cycloalkyl which may be substituted with 1-3 substituents    selected from the class consisting of a halogen, an optionally    halogenated lower (C₁₋₄) alkyl and a phenyl-lower (C₁₋₄) alkyl,    which may contain a hetero-atom selected from the class consisting    of a sulfur atom, an oxygen atom and a nitrogen atom, which may be    fused with a benzene ring and which may be crosslinked via    straight-chained, atom chain having the carbon number of 1 to 2    (e.g., cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,    tetrahydropyranyl, tetrahydrothiapyranyl, piperidinyl, indanyl,    tetrahydronaphthalenyl, bicyclo[2.2.1]heptyl, etc., each of which    may be substituted); etc.

In the above formula (eId), examples of the “optionally substitutedalicyclic (non-aromatic) heterocyclic group” represented by Re^(2d) andR^(e3d) include 5- to 6-membered non-aromatic heterocyclic ringcontaining 1 to 4 hetero-atoms consisting of 1 to 2 kinds ofhetero-atoms selected from nitrogen atom, sulfur atom and oxygen atomsuch as tetrahydrofuran, tetrahydrothiophene, dioxolane, dithiolane,oxathiolane, pyrrolidine, pyrroline, imidazolidine, imidazoline,pyrazolidine, pyrazoline, piperidine, piperazine, oxazine, oxadiazine,thiazine, thiadiazine, morpholine, thiomorpholine, pyran,tetrahydropyran, tetrahydrothiopyran, etc., preferably, a 5- to6-membered non-aromatic heterocyclic ring containing 1 hetero-atom suchas tetrahydrofuran, piperidine, tetrahydropyran, etc., or the like.

Examples of the substituent, which the “alicyclic heterocyclic group” inthe “optionally substituted alicyclic heterocyclic group” represented byR^(e2d) and R^(e3d) may have, include halogen (e.g. fluorine, chlorine,bromine, iodine, etc.), an optionally halogenated lower (C₁₋₄) alkyl, anoptionally halogenated C₁₋₄ alkoxy (e.g., methoxy, ethoxy, propoxy,butoxy, trifluoromethoxy, trifluoroethoxy, etc.), C₁₋₄ alkylenedioxy(e.g., —O—CH₂—O—, —O—CH₂—CH₂—O—, etc.), formyl, C₂₋₄ alkanoyl (e.g.,acetyl, propionyl, etc.), C₁₋₄ alkylsulfonyl (e.g., methanesulfonyl,ethanesulfonyl, etc.), phenyl-lower (C₁₋₄) alkyl, C₃₋₇ cycloalkyl,cyano, nitro, hydroxy group, an optionally substituted thiol group (e.g.thiol, C₁₋₄ alkylthio, etc.), an optionally substituted amino group(e.g. amino, mono-C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, 5- to 6-memberedcyclic amino such as tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole, imidazole, etc., etc.), anoptionally esterified or amidated carboxyl group (e.g. carboxyl, C₁₋₄alkoxy-carbonyl, carbamoyl, mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄alkylcarbamoyl, etc.), a lower (C₁₋₄) alkoxy-carbonyl, oxo group(preferably, halogen, an optionally halogenated lower (C₁₋₄) alkyl, anoptionally halogenated lower (C₁₋₄) alkoxy, phenyl-lower (C₁₋₄) alkyl,C₃₋₇ cycloalkyl, cyano, hydroxy group, etc.), etc., and the number ofthe substituents are preferably 1 to 3.

Among them, as R^(e2d), an optionally substituted acyclic hydrocarbongroup (e.g., alkyl, alkenyl, etc., each of which may be substituted) ispreferable, an optionally substituted lower C₁₋₆ alkyl group is morepreferable, and in particular, an optionally substituted methyl group ispreferable.

As R^(e3d), an optionally substituted alicyclic hydrocarbon group (e.g.,cycloalkyl, cycloalkenyl, etc., each of which may be substituted;preferably, an optionally substituted lower C₃₋₈ cycloalkyl group; andmore preferably, an optionally substituted cyclohexyl) or an optionallysubstituted alicyclic heterocyclic group (preferably, an optionallysubstituted saturated alicyclic heterocyclic group (preferably, 6membered ring group)); more preferably, an optionally substitutedtetrahydropyranyl, an optionally substituted tetrahydrothiopyranyl or anoptionally substituted piperidyl; and in particular, an optionallysubstituted tetrahydropyranyl) is preferable.

The compound represented by the formula (IV) may be hydrated, and thecompound represented by the formula (IV), the salt thereof and thehydrate thereof are hereinafter referred to as Compound (IV).

Compound (IV) can be produced, for example, by the following manner.

Production Method 1

As shown by the following formula, Compound (IV) can be produced byreacting a compound of the formula (IId) or a salt thereof (hereinafterreferred to as Compound (IId)) with a compound represented by theformula (IIId), a salt thereof or a reactive derivative thereof at thecarboxyl group hereinafter referred to as Compound (IIId).

wherein each symbol has the same meaning given above.

Examples of the reactive derivative at the carboxyl group of a compoundrepresented by the formula (IIId) which can be used in an acylatingreaction include, for example, an acid halide, an acid azide, an acidanhydride, a mixed acid anhydride, an active amide, an active ester, anactive thio ester, an isocyanate, etc. Examples of the acid halideinclude, for example, an acid chloride, an acid bromide, etc.; examplesof the mixed acid anhydrides include a mono-C₁₋₆ alkyl-carbonic acidmixed acid anhydride (e.g. a mixed acid anhydride of free acid andmonomethylcarbonic acid, monoethylcarbonic acid, mono-isopropylcarbonicacid, mono-isobutylcarbonic acid, mono-tert-butylcarbonic acid,mono-benzylcarbonic acid, mono-(p-nitrobenzyl)carbonic acid,mono-allylcarbonic acid, etc.), a C₁₋₆ aliphatic carboxylic acid mixedacid anhydride (e.g. a mixed acid anhydride of free acid and aceticacid, trichloroacetic acid, cyanoacetic acid, propionic acid, butyricacid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid,trifluoroacetic acid, trichloroacetic acid, acetoacetic acid, etc.), aC₇₋₁₂ aromatic carboxylic acid mixed acid anhydride (e.g. a mixed acidanhydride of free acid and benzoic acid, p-toluic acid, p-chloro benzoicacid, etc.), an organic sulfonic acid mixed acid anhydride (e.g. mixedacid anhydride of free acid and methanesulfonic acid, ethanesulfonicacid, benzenesulfonic acid, p-toluenesulfonic acid, etc.) etc.; examplesof the active amide include an amide with a nitrogen-containingheterocyclic compound (an acid amide of a free acid and, for example,pyrazole, imidazole, benzotriazole, etc., these nitrogen-containingheterocyclic compound may be substituted with a C₁₋₆ alkyl group (e.g.,methyl, ethyl, etc.), a C₁₋₆ alkoxy group (e.g., methoxy, ethoxy, etc.),a halogen atom (e.g., fluorine, chlorine, bromine, etc.), an oxo group,a thioxo group, a C₁₋₆ alkylthio group (e.g., methylthio, ethylthio,etc.), etc.), etc.

As an active ester, all the active esters used in the field of thesynthesis of β-lactam and peptide may be used. Examples of the activeester include, for example, an organic phosphoric acid ester (e.g.diethoxyphosphoric acid ester, diphenoxyphosphoric acid ester, etc.),p-nitrophenyl ester, 2,4-dinitrophenyl ester, cyanomethyl ester,pentachlorophenyl ester, N-hydroxysuccinimide ester,N-hydroxyphthalimide ester, 1-hydroxybenzotriazole ester,6-chloro-1-hydroxybenzotriazole ester, 1-hydroxy-1H-2-pyridone ester,etc. Examples of the active thio ester include an ester of the acid withan aromatic heterocyclic thiol compound (e.g. 2-pyridylthiol ester,2-benzothiazolylthiol ester, etc., which heterocyclics may besubstituted with a C₁₋₆alkyl group (e.g. methyl, ethyl, etc.), aC₁₋₆alkoxy group (e.g., methoxy, ethoxy, etc.), a halogen atom (e.g.,fluorine, chlorine, bromine, etc.), a C₁₋₆alkyl-thio group (e.g.,methylthio, ethylthio, etc.), etc.).

Examples of the leaving group represented by L include, for example, ahalogen atom (e.g., a chlorine atom, a bromine atom, an iodine atom,etc.), an alkyl- or aryl-sulfonyloxy group (e.g., methanesulfonyloxy,trifluoromethanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy,p-toluenesulfonyloxy, etc.), etc.

The reaction is usually carried out in a solvent inert to the reaction.Examples of the use for the solvent include an ether solvent (e.g.,ethyl ether, diisoprpyl ether, dimethoxy ethane, tetrahydrofuran,dioxane, etc.), a halogenated solvent (e.g., dichloromethane,dicholoroethane, chloroform, etc.), an aromatic solvent (e.g., toluene,chlorobenzene, xylene, etc.), acetonitrile, N,N-dimethylformamide (DMF),acetone, methylethyl ketone, dimethylsulfoxide (DMSO), water, etc., or amixed solvent thereof. Among them, acetonitrile, dichloromethane,chloroform, etc. are preferable. The reaction is usually carried out byusing 1 to 5 equivalent, preferably 1 to 3 equivalents of Compound(IIId) relative to 1 equivalent of Compound (IId). The reactiontemperature ranges from −20° C. to 50° C., preferably 0° C. to roomtemperature, and reaction time is usually 5 minutes to 100 hours. Thereaction may smoothly proceed by using a base. As the base, an inorganicbase and an organic base can be used effectively. Examples of theinorganic base include a hydroxide, a hydride, a carbonate, abicarbonate of alkaline metal or alkaline earth metal. Among them,potassium carbonate, sodium carbonate, sodium hydroxide, potassiumhydroxide, sodium hydrogencarbonate, potassium hydrogencarbonate arepreferable. Examples of the organic base preferably include a tertiaryamine such as triethylamine. Examples of the reactive derivative at thecarboxyl group of the formula (IIId) are as mentioned above, and amongthem, an acid halide is preferable. The used amount of the base isusually 1 to 10 equivalents, preferably 1 to 3 equivalents relative to 1equivalent of Compound (IId).

The acylation reaction in which a carboxylic acid is used is carried outin an inert solvent (e.g., a halogenated solvent, acetonitrile) byreacting one equivalent of Compound (IId) with 1 to 1.5 equivalent ofcarboxylic acid (A^(d)—CO₂H) in the presence of 1 to 1.5 equivalent ofdehydrating condensation agent such as dicyclohexyl carbodiimide (DCC),etc. The reaction is usually carried out at room temperature, and thereaction time is 0.5 to 24 hours.

Compound (IIId) used as the starting material in the reaction can beproduced by a conventional manner using a compound described inHeterocycles, 43(10) 2131-2138 (1996) etc. as a starting compound.Compound (IId) used in the method can be produced by a manner describedin Chem. Pharm. Bull. 47(1) 28-36 (1999) or Japanese unexamined patentpublication No. 53654/1981 or a similar manner thereof.

Compound (IId) wherein rd is 3 can be produced, for example, by a methoddescribed in Synthetic Comm., 1991, 20, 3167-3180.

That is, the above compound can be produced by the following method byapplying an addition reaction of amines or amides to unsaturated bond.

wherein each symbol has the same meaning as defined above.

The compound can be produced by reacting acrolein derivatives (VId) withCompound (Vd), followed by reacting the resulting compound (VIId) withCompound (VIIId) under a condition of reduction. The reaction ofCompound (VId) with Compound (Vd) is usually carried out in a solventinert to the reaction in the presence of a base. Examples of the baseinclude 1) a strong base such as hydride of alkali metal or alkalineearth metal (e.g., lithium hydride, sodium hydride, potassium hydride,calcium hydride, etc.), an amide of an alkali metal or an alkaline earthmetal (e.g., lithium amide, sodium amide, lithium diisopropylamide,lithium dicyclohexylamide, lithium hexamethyldisilazide, sodiumhexamethyldisilazide, potassium hexamethyldisilazide, etc.), a loweralkoxide of alkali metal or alkaline earth metal (e.g., sodiummethoxide, sodium ethoxide, potassium t-butoxide, etc.), etc., 2) aninorganic base such as a hydroxide of an alkali metal or an alkalineearth metal (e.g., sodium hydroxide, potassium hydroxide, lithiumhydroxide, barium hydroxide, etc.), a carbonate of an alkali metal or analkaline earth metal (e.g., sodium carbonate, potassium carbonate,cesium carbonate, etc.), a bicarbonate of alkali metal or alkaline earthmetal (e.g., sodium hydrogencarbonate, potassium hydrogencarbonate,etc.), etc., 3) an organic base etc., such an amine as triethylamine,diisopropylethylamine, N-methylmorpholine, dimethylaminopyridine,DBU(1,8-diazabicyclo[5.4.0]-7-undecene),DBN(1,5-diazabicyclo[4.3.0]non-5-ene), etc., etc., and such basicheterocyclic Compound, etc., as pyridine, imidazole, 2,6-lutidine, etc.Examples of the solvent include those mentioned in the reaction ofCompound (IId) with Compound (IIId). These solvents can be used solelyor in combination. Compound (VIId) can be obtained in the reaction.

In the reaction between Compound (VIId) and Compound (VIIId), examplesof the reducing agent include sodium borohydride, lithium borohydride,sodium borocyanohydride, sodium borotriacetooxyhydride, etc. The amountof the reducing agent used is usually 1 to 10 equivalent relative to 1equivalent of Compound (VIId), preferably 1 to 4 equivalent. Thereaction temperature is −20 to 50° C. preferably 0° C. to ambienttemperature, and the reaction time is 0.5 to 24 hours.

The reaction can also be carried out by a catalytic reduction reaction.

The catalytic reduction reaction is carried out in the presence of acatalytic amount of a metal catalyst such as Raney nickel, platinumoxide, metallic palladium, palladium-carbon, etc., in an inert solvent(e.g., an alcohol solvent such as methanol, ethanol, isopropanol,t-butanol, etc.), at room temperature to 100° C., under a hydrogenpressure of 1 to 100 atm for 1 to 48 hours to produce Compound (IIda).

Production Method 2

As shown below, Compound (IV) can be produced by reacting a compound(IVd) or its salt (herein after referred to as Compound (IVd)) with acompound (Vd) or its salt (herein after referred to as Compound (Vd)).

wherein L^(d) is a leaving group, and the other symbols have the meaninggiven above.

Examples of the leaving group represented by L^(d) include, for example,a halogen atom (e.g., a chlorine atom, a bromine atom, an iodine atom,etc.), an alkyl or arylsulfonyloxy group (e.g., methanesulfonyloxy,trifluoromethanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy,p-toluenesulfonyloxy, etc.), etc.

The reaction can be carried out by a manner similar to that described inOrganic Functional Group Preparations 2nd ed., (Academic Press, Inc.).

The reaction is usually carried out in a solvent inert to the reaction.Examples of the solvent include an alcohol solvent, an ether solvent, ahalogenated solvent, an aromatic solvent, acetonitrile,N,N-dimethylformamide (DMF), acetone, methylethyl ketone,dimethylsulfoxide (DMSO), etc. These solvents can be used solely or incombination. Among them, acetonitrile, dimethylformamide, acetone,ethanol, etc., are preferable. The reaction temperature ranges usuallyfrom room temperature to 100° C., preferably from room temperature to50° C., and the reaction time is usually 0.5 to 1 day. In this reaction,a base is usually added in an amount of 1 to 3 equivalents relative to 1equivalent of Compound (IVd), but it is not essential. Examples of thebase include those mentioned in the reaction of Compound (IId) withCompound (IIId).

Compound (IVd) used as the starting material in this reaction can beproduced by a known conventional manner with the use of Compound (IIId)as a starting material. Examples of the salt of a compound of theformulas (I). (II), (III), (IV) and (eI) of the present inventioninclude an acid addition salt such as a salt of an inorganic acid (e.g.,hydrochloric acid salt, sulfuric acid salt, hydrobromic acid salt,phosphoric acid salt, etc.), a salt of an organic acid (e.g., aceticacid salt, trifluoroacetic acid salt, succinic acid salt, maleic acidsalt, fumaric acid salt, propionic acid salt, citric acid salt, tartaricacid salt, lactic acid salt, oxalic acid salt, methanesulfonic acidsalt, p-toluenesulfonic acid salt, etc.), etc., a salt with a base (e.g.an alkali metal salt such as potassium salt, sodium salt, lithium salt,etc., an alkaline earth metal salt such as calcium salt, magnesium salt,etc., ammonium salt, a salt with an organic base such as trimethylaminesalt, triethylamine salt, tert-butyl dimethylamine salt, dibenzylmethylamine salt, benzyl dimethylamine salt, N,N-dimethylaniline salt,pyridine salt, quinoline salt, etc.).

Compounds represented by the aforementioned formulas (I), (II), (III),(IV) and (eI) or salts thereof have a CCR antagonist effect, andparticularly a CCR 5 antagonist effect, a CXCR4 antagonist effect, aCXCR3 antagonist effect, a CCR2 antagonist effect, and a CCR3 antagonisteffect, and in order to reduce toxicity or side effects, can beadministered orally or non-orally alone, or combined with apharmaceutically acceptable carrier to form a pharmaceutical preparationsuch as a solid preparation such as tablets, capsules, granules andpowders; or a liquid preparation such as a syrups and injectablepreparations.

Examples of non-oral forms of administration include injections,intravenous drips, suppositories, rectal suppositories, vaginalsuppositories, and the like.

Commonly used organic or inorganic substances may be employed asingredients of the pharmaceutically acceptable carrier, and may becombined with excipients, lubricants, binders, and disintegrators insolid preparations, and solvents, solubilizers, suspending agents,isotonizing agents, buffers, analgesic agents and the like in liquidpreparations. Additives such as preservatives, antioxidants, colorants,sweeteners and the like may also be added according to need. Examples ofsuitable excipients include lactose, sugar, D-mannitol, starch, cornstarch, crystalline cellulose, light silicic anhydride and the like.Examples of suitable lubricants include magnesium stearate, calciumstearate, talc, colloidal silica, and the like. Examples of suitablebinders include crystalline cellulose, sugar, D-mannitol, dextrin,hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, and the like. Examples of suitable disintegrators includestarch, carboxymethyl cellulose, calcium carboxymethyl cellulose,croscarmellose sodium, sodium carboxymethyl starch, and the like.Examples of suitable solvents include water for injection, alcohol,propylene glycol, sesame oil, corn oil, and the like. Examples ofsuitable solubilizers include polyethylene glycol, propylene glycol,D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol,triethanolamine, sodium carbonate, sodium citrate, and the like.Examples of suitable suspending agents include surfactants such asstearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionicacid, lecithin, benzalkonium chloride, benzethonium chloride, glycerolmonostearate, and the like; hydrophilic polymers such as polyvinylalcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium,methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, and the like. Examples of suitable isotonizingagents include sodium chloride, glycerol, D-mannitol, and the like.Examples of suitable buffers include buffer solutions of phosphate,acetate, carbonate, citrate, and the like. Examples of suitableanalgesic agents include benzyl alcohol and the like. Examples ofsuitable preservatives include para-hydroxybenzoate esters,chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid,sorbic acid, and the like. Examples of suitable antioxidants includesulfite salts, ascorbate salts, and the like.

Pharmaceutical compositions containing a compound represented by theaforementioned formulas (I), (II), (III), (IV) and (eI) or a saltthereof can be employed as an agent for the prevention and treatment ofa variety of diseases, such as an agent for the prevention and treatmentof graft-versus-host disease during organ transplantation and/orrejection reactions, an agent for the prevention and treatment forrheumatoid arthritis, autoimmune disease, allergy disorders, ischemicbrain cell damage, myocardial infarction, chronic nephritis, andarteriosclerosis, and the like. Examples of the diseases that aretargeted by the preventative and therapeutic agent of the presentinvention include transplant rejection reactions (post-transplantrejection reactions, post-transplant polycythemia/hypertension/organdamage/vascular thickening, graft-versus-host disease, and the like),arthritic bone diseases including osteomyelitis and the like (chronicrheumatoid arthritis, deforming arthritis, rheumatoid myelitis,osteoporosis, abnormal growth of cells and the like, bone fractures,refractures, osteomalacia, Behcet's syndrome of bone, ankylosingspondylitis, joint tissue destruction caused by deformation gonarthritisand related diseases, and the like), autoimmune diseases (collagendisease, systemic lupus erythematosus, scleroderma, polyarteritis,myasthenia gravis, multiple sclerosis, and the like), allergic disorders(allergic rhinitis, conjunctivitis, gastrointestinal tract allergies,pollinoisis, anaphylaxis, atopic dermatitis, bronchial asthma, and thelike), inflammatory bowel diseases (ulcerative colitis, Crohn's disease,gastritis, gastric ulcer, post-operative gastric injury, dyspepsia,esophageal ulcer, pancreatisis, stress-induced gastric ulcer, colonpolyps, cholelithiasis, hemorrhoidial disease, peptic ulcer, regionalileitis, and the like), inflammatory diseases (retinopathy,post-surgical/injury inflammation, reduction of swelling, pharyngitis,cystitis, meningitis, inflammatory ophthalmopathy, and the like),respiratory diseases (colds, pneumonia, asthma, pulmonary hypertension,pulmonary thrombosis, pulmonary embolism, pulmonary sarcoidosis,tuberculosis, interstitial pneumonia, silicosis, adult respiratorydistress syndrome, chronic obstructive pulmonary disease, and the like),infectious diseases (viral infections such as cytomegalovirus, influenzavirus, herpes virus, rickettsia infection, bacterial infection, sexuallytransmitted disease, pneumocystis carini pneumonia, Helicobactor pyloriinfection, systemic mycosis, tuberculosis, invasive staphylococcalinfection, acute viral infection, acute bacterial infection, AIDSencephalopathy, septicemia, sepsis, severe sepsis, septic shock,endotoxic shock, toxic shock syndrome, and the like), carcinoma andcachexia accompanying the same, metastatic cancer (bladder cancer,breast cancer, uterine and cervical cancer, ovarian cancer, chroniclymphocytic leukemia, chronic myelogenous leukemia, colon cancer, rectalcancer, colorectal cancer, multipule myeloma, malignant myeloma,prostate cancer, lung cancer, stomach cancer, Hodgkin's disease,malignant melanoma, malignant lymphoma, and the like), non-Hodgkin'slymphoma, non-small cell lung cancer, malignant melanoma,neurodegenerative diseases (Alzheimer's disease, Parkinson's disease,amyotrophic lateral sclerosis (ALS), Huntington's chorea, diabeticneuropathy, Creutzfeldt-Jakob disease, and the like), psychiatricdiseases (depression, epilepsy, dipsomania, and the like),schizophrenia, vascular insufficiency, central nervous system injury(injury due to cerebral hemorrhage and cerebral infarction as well asaftereffects/complications thereof, head injury, spinal cord injury,cerebral edema, injury to sensory functions, abnormal sensory functions,injury to the autonomic nervous system, abnormal autonomic nervoussystem, and the like), central injury (heat injury, spinal injury,whiplash, and the like), vascular dementia (multiinfarct dementia,Binswanger's disease, and the like), cerebrovascular injury(asymptomatic cerebrovascular injury, transient cerebral ischemicattack, cerebral accident, multiinfarct dementia, hypertensiveencephalopathy, and the like), reoccurrence and after-effects ofcerebrovascular injury (neurotic disorders, psychological disorders,subjective symptoms, disruptions to daily living activities, and thelike), decline in central functions after multiinfarct dementia andcerebrovascular blockage, injury or abnormalities to the auto-modulationof cerebral circulation/renal circulation, injury to the blood-brainbarrier, anxiety, acute coronary artery disease syndrome such asunstable angina, dysphoric psychological states, amnesia, trigeminalneuralgia, otorhinological diseases (Meniere's syndrome, tinnitus,injuries to the gustatory sense, dysphagia, and the like), migraineheadache, chronic pain (keloid, hemangioma, psoriasis, and the like),arteriosclerosis obliterans, thromboangiitis obliterans, peripheralarterial occlusion, postischemic reperfusion injury, Raynaud's disease,Buerger disease, myocarditis, cardiac ischemia, cardiac infarction,progressive cardiac insufficiency after cardiac infarction,cardiomyopathy, cardiomegaly, chronic cardiac insufficiency includingacute cardiac insufficiency and congestive heart failure, angina,arrhythmia, tachycardia, abnormal diurnal variation in blood pressure,abnormal blood/blood cell properties (platelet hyperagglutination,abnormally deformed red blood cells, white blood cell hyperadhesion,increase in blood viscosity, polycythemia, vascular peliosis, autoimmunehemolytic anemia, disseminated intravascular coagulation syndrome,multiple myeloma, and the like), athero and arteriosclerosis (aneurism,coronary artery sclerosis, cerebral artery sclerosis, peripheralarteriosclerosis, and the like), post-bypass surgery vascularreocclusion/restenosis, post-intervention (percutaneous transluminalcoronary angioplasty, stent placement, coronary artery endoscope,endovascular ultrasound, coronary thrombolysis therapy, and the like)vascular thickening or occlusion and organ damage, production andhyperactivity of vasoactive substances and thrombosis inducers(endothelin, thromboxane A2, and the like), angiogenesis (includingabnormal angiogenesis during abnormal capillary network formation inatherosclerotic lesions), thrombosis, fat deposit promotion,ophthalmopathy (glaucoma, high ocular pressure, and the like),hypertension, hypertensive tinnitus, dialytic hypotension, endothelialcell and organ derangement, endocrine diseases (Addison's disease,Cushing's disease, pheochromoctyoma, primary hyperaldosteronism, and thelike), nephritis, renal diseases (nephritis, glomerulonephritis,glomerulosclerosis, renal insufficiency, thrombotic microangiopathy,dialysis complications, organopathy including nephropathy due toradiation exposure, diabetic nephropathy, and the like), diabeticdiseases (insulin dependent diabetes, diabetic complications, diabeticretinopathy, diabetic microangiopathy, diabetic neuropathy, and thelike), glucose tolerance abnormalities, liver diseases (hepatitis andchronic hepatitis, hepatocirrhosis, and the like), interstitial liverdisease, chronic pancreatitis, portal hypertension, obesity, maleinfertility, gynecological diseases (menopausal disorders, gestosis,endometriosis, uterine myoma, ovarian diseases, mammary diseases, andthe like), swelling, chronic fatigue syndrome, prostatomegaly, Behcetdisease, Hodgkin's disease, Lacunar blockages, impaired consciousness,psoriasis, diseases due to environmental/vocational causes (radiationdamage, damage caused by ultravioletrays/infrared rays/laser light,altitude sickness, and the like), claudicatio intermittens, and thelike.

Pharmaceutical compositions that contain the compounds represented bythe aforementioned formulas (I), (II), (III), (IV) and (eI) or saltsthereof will differ according to the type of disease being targeted, butmay be employed in combination with other drugs. Examples of those otherdrugs include HDL enhancers [squalene synthase inhibitors, CEPTinhibitors, LPL activators, and the like], agents for the prevention andtreatment of HIV infection [nucleoside reverse transcriptase inhibitorssuch as zidovudine, didanosine, zalcitabine, lamivudine, stavudine,abacavir, adefovir, adefovir dipivoxil, fozivudine tidoxil, and thelike, non-nucleoside reverse transcriptase inhibitors such asnevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, andthe like, and protease inhibitors such as saquinavir, ritonavir,indinavir, nelfinavir, amprenavir, palinavir, lasinavir, lopinavir, andthe like], HMG-CoA reductase inhibitors: cerivastatin, atorvastatin,pravastatin, simvastatin, itavastatin, lovastatin, fluvastatin,(+)-3R,5S-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)pyrimidin-5-yl]3,5-dihydroxy-6(E)-heptenoicacid, and the like, atopic dermatitis therapeutic agents [sodiumchromoglycate and the like], allergic rhinitis therapeutic agents[sodium chromoglycate, chlorphenylamine maleate, alimemazine tartrate,clemasine fumarate, homochlorocyclizine hydrochloride, terfenadine,mequitazine, and the like], imipenem cilastatin sodium, endotoxinantagonists or antibodies, oxidosqualene-lanosterol cylase [e.g.,decalin derivatives, azadecalin derivatives, and indane derivatives],calcium antagonists (diltiazem and the like), glycerol, choline esteraseinhibitors (e.g., Aricept (donepezil) and the like), compounds whichsuppress cholesterol absorption (e.g., sitosterol, neomycin, and thelike), compounds which inhibit cholesterol production [e.g., HMG-CoAreductase inhibitors such as lovastatin, simvastatin, pravastatin, andthe like], cyclooxygenase suppressors [(Cox-I, Cox-II suppressors) e.g.,celecoxib, rofrcoxib, salicylic acid derivatives such as aspirin or thelike, diclofenac, indomethacin, loxoprofen, and the like], signaltransduction inhibitors, squalene epoxidase inhibitors [e.g., NB-598,related compounds and the like], steroids [e.g., dexamethasone,hexestrol, methimazole, betamethasone, triamcinolone, triamcinoloneacetonide, fluocinonide, fluocinolone acetonide, prednisolone,methylprednisolone, cortisone acetate, hydrocortisone, fluorometholone,beclometasone dipropionate, estriol, and the like], diacerin, niacin,derivatives thereof and analogues thereof [e.g., acipimox and probucol],nicerogolin, therapeutic agents for nephrotic syndrome: prednisolone(Predonine), prednisolone sodium succinate (Predonine), sodiummethylprednisolone succinate (Solu-Medrol), betamethasone (Rinderon),dipyridamole (Persantine), dilazep hydrochloride (Comelian),ticlopidine, clopidogrel, antiplatelet drugs such as FXa inhibitors andthe like and anticoagulant drugs, barbital type anticonvulsant drugs oranesthetics (phenobarbital, mephobarbital, metharbital, and the like),therapeutic agents for Parkinson's disease (e.g., L-dopa and the like),histamine receptor blocking agents (cimetidine, famotidine, and thelike), hydantoin type anticonvulsant drugs (phenyloin, mephenyloin,ethotoin, and the like), hydroxycam, fibrates (e.g, clofibrate,benzafibrate, gemfibrozil, and the like), prostaglandins, megestrolacetate, therapeutic agents for gastric and duodenal ulcers: antacids[e.g., histamine H2 antagonists (cimetidine and the like), proton pumpinhibitors (lansoprazole and the like), and the like], inflammatorymediator effect suppressants, coronary vasodilators: nifedipine,diltiazem, nicorandil, nitrous acid agents, and the like, therapeuticagents for infection: [e.g., antibiotics (cefotiam dihydrochloride,cefozopran hydrochloride, ampicillin, and the like), chemotherapeuticagents (sulfa drugs, synthetic antibacterial drugs, anti-viral drugs,and the like), biological preparations (vaccines, blood preparationssuch as immunoglobulin and the like) and the like] and the like,therapeutic agents for liver disease: glycyrrhizin preparations [e.g.,stronger minophagen and the like], liver hydrolyzate, SH compounds[e.g., glutamines and the like], special amino acid preparations [e.g.,aminoleban and the like], phosphatides [e.g., polyenephosphatidylcholineand the like], vitamins [e.g., vitamins B1, B2, B6, B12, C and thelike], adrenal cortical hormones [e.g., dexamethasone, betamethasone,and the like], interferon [e.g., interferon α, interferon β, and thelike], therapeutic agents for hepatic encephalopathy [e.g., lactuloseand the like], hemostatic agents employed during esophageal and gastricvarix ruptures [e.g., vasopressin, somatostatin, and the like], and thelike, therapeutic agents for arthritis, muscle relaxants [pridinol,tubocurarine, pancuronium, tolperisone hydrochloride, chlorphenesincarbamate, baclofen, chlormezanone, mephenesin, chlorzoxazone,eperisone, tizanidine, and the like], vasodilators [oxyphedrin,diltiazem, tolazoline, hexobendine, bamethan, clonidine, methyldopa,guanabenz, and the like], vasoconstrictors [dopamine, dobutaminedenopamine, and the like], blood platelet aggregant suppressors (ozagreland the like), agents for preventing or treating thrombus formation:anticoagulants [e.g., heparin sodium, heparin calcium, warfarin calcium(warfarin), Xa inhibitors], thrombolytic agents [e.g., tPA, urokinase],antiplatelet agents [e.g., aspirin, sulfinpyrazone (Anturan),dipyridamole (Persantin), ticlopidine (Panaldine), cilostazol (Pletal),GPIIb/IIIa antagonists (Rheopro)], antidepressant drugs [imipramine,chlomipramine, noxiptiline, phenelzine, amitriptyline hydrochloride,nortriptyline hydrochloride, amoxapine, mianserin hydrochloride,maprotiline hydrochloride, sulpiride, fluvoxamine maleate, trazodonehydrochloride, and the like], antiepileptic drugs [gabapentin,phenyloin, ethosuximide, acetazolamide, chlordiazepoxide, trimethadione,carbamazepine, phenobarbital, primidone, sulthiame, sodium valproate,clonazepam, diazepam, nitrazepam, and the like], antiallergic drugs,[diphenhydramine, chlorpheniramine, tripelennamine, methdilamine,clemizole, diphenylpyraline, methoxyphenamine, sodium cromoglycate,tranilast, Repriinast, Amlexanox, ibudilast, ketotifen, terfenadine,mequitazin, azelastine, epinasine, ozagrel hydrochloride, pranlkasthydrate, seratrodast, fexofenadine, ebastine, Bucillamine, Oxatomide,Stronger Neo-Minophagen, tranexamic acid, ketotifen fumarate, and thelike], cholilytic drugs (e.g., ipratropium bromide, flutropium bromide,oxyphenonium bromide, and the like), anti-Parkinson's drugs (dopamine,levodopa, and the like), anti-rheumatic drugs, anti-inflammation agents(e.g., aspirin, acetaminophen, diclofenac sodium, ibuprofen,indomethacin, loxoprofen sodium, dexamethasone, and the like),anticoagulant drugs and anti-platelet drugs [sodium citrate, activatedprotein C, tissue factor path inhibitors, antithrombin III, dalteparinsodium, argatroban, gabexate, ozagrel sodium, ethyl icosapenate,beraprost sodium, alprostadil, pentoxyfylline, tisokinase,streptokinase, heparin, and the like], anticoagulation therapy agents[dipyridamole (Persatine), dilazep hydrochloride (Comelian),ticlopidine, clopidogrel, Xa inhibitors], antibacterial drugs [(i) sulfadrugs [sulfamethizole, sulfisoxazole, sulfamonomethoxine,sulfamethizole, salazosulfapyridine, sulfadiazine silver, and the like],(ii) quinoline type antibiotics [nalidixic acid, pipemidic acidtrihydrate, enoxacin, norfloxacin, ofloxacin, tosufloxacin tosilate,ciprofloxacin hydrochloride, lomefloxacin hydrochloride, sparfloxacin,fleroxacin, and the like], (iii) antituberculosis drugs [isoniazid,ethambutol ethambutol hydrochloride]]], p-aminosalicylic acid (calciumparaminosalicylate), pyrazinamide, ethionamide, protionamide,rifampicin, streptomycin sulfate, kanamycin sulfate, cyclocerine, andthe like], (iv) antiacidfast bacterium drugs [diaphenylsulfone,rifampicin, and the like], (v) antiviral drugs [idoxuridine, aciclovir,aminopterine, vidarabine, ganciclovir, and the like], (vi) anti-HIVdrugs [zidovudine, didanosine, zalcitabine, indinavir sulfate ethanoladduct, ritonavir, and the like], (vii) antispirochetic drugs, (viii)antibiotics [tetracycline hydrochloride, ampicillin, piperacillin,gentamicin, dibekacin, kanendomycin, lividomycin, tobramycin, amikacin,fradiomycin, sisomicin, tetracycline, oxytetracycline, rolitetracycline,doxycycline, ampicillin, piperacillin, ticarcillin, cefalothin,cephapirin, cephaloridine, cefaclor, cephalexin, cefroxadine,cefadroxil, cefamandole, cefotiam, cefuroxime, cefotiam, cefotiamhexetyl, cefuroxime axetil, cefdinir, cefditoren pivoxil, ceftazidime,cefpiramide, cefsulodin, cefinenoxime, cefpodoxime proxetil, cefpirome,cefozopran, cephem, cefsulodin, cefinetazole, cefminox, cefoxitin,cefbuperazone, latamoxef, flomoxef, cefazolin, cefotaxime, cefoperazone,ceftizoxime, moxalactam, thienamycin, sulfazecin, azthreonam, or saltsthereof, griseofulvin, lankacidins [Journal of Antibiotics, 38, 877-885(1985)] and the like], cefixime, levofloxacin], antithrombosis agents(argatroban and the like), antiprotozoan drugs [metronidazole,tinidazole, diethylcarbamazine citrate, quinine hydrochloride, quininesulfate, and the like], antineoplastic drugs[6-O—(N-chloroacetylcarbamoyl) fumagillol, bleomycin, methotrexate,actinomycin D, mitomycin C, daunorubicin, adriamycin, neocarzinostatin,cytosine arabinoside, fluorouracil, tetrahydrofuryl-5-fluorouracil,picibanil, lentinan, levamisole, bestatin, azimexon, glycyrrhizin,doxorubicin hydrochloride, aclarubicin hydrochloride, bleomycinhydrochloride, hexoprenaline sulfate, vincristine sulfate, vinblastinesulfate, irinotecan hydrochloride, cyclophosphamide, melphalan,busulphan, thiotepa, procarbazine hydrochloride, cisplatin,azathioprine, mercaptopurine, tegafur, carmofur, cytarabine,methyltestosterone, testosterone propionate, testosterone enanthnate,mepitiostane, fosfestrol, chlormadinone acetate, leuprolide acetate,buserelin acetate, and the like], antifungal drugs [(i) polyethylenetype antibiotics (e.g., amphotericin B, nystatin, trichomycin), (ii)griseofulvin, pyrrolnitrin, and the like, (iii) cytosine antimetabolites(e.g., flucytosine), (iv) imidazole derivatives (e.g., econazole,clotrimazole, miconazole nitrate, bifonazole, cloconazole), (v) triazolederivatives (e.g., fluconazole, itraconazole, azole compounds[2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluorobenzene)phenyl-3-(2H,4H)-1,2,4-triazolam],(vi) thiocarbamic acid derivatives (e.g., trinaphthol), (vii)echinocandin derivatives (e.g., caspfungin, FK-463, V-echinocandin) andthe like], antipsychotic drugs [chlorpromazine hydrochloride,prochloroperazine, trifluoperazine, thioridazine hydrochloride,perphenazine maleate, fluphenazine enanthate, prochlorperazine maleate,levomepromazine maleate, promethazine hydrochloride, haloperidol,bromperidol, spiperone, recerpine, clocapramine hydrochloride,sulpiride, zotepine, and the like], antiulcer drugs [metoclopramide,histidine hydrochloride, lansoprazole, metoclopramide, pirenzepine,cimetidine, ranitidine, famotidine, urogastrine, oxethazaine,proglumide, omeprazole, sucralfate, sulpiride, cetraxate, gefarnate,aldioxa, teprenone, prostaglandin, and the like], anti-diabetes agents(e.g., pioglitazone, nateglinide, voglibose, acarbose, and the like),antiobestic drug (mazindol and the like), antirheumatic drugs and thelike, antianxiety drugs [diazepam, lorazepam, oxazepam,chlordiazepoxide, medazepam, oxazolam, cloxazolam, clotiazepam,bromazepam, etizolam, fludiazepam, hydroxyzine, and the like],antiarrhythmic drugs: disopyramide, lidocaine, quinidine sulfate,flecainide acetate, mexiletine hydrochloride, amitriptylinehydrochloride, and β-blockers, Ca antagonists and the like,antiasthmatic drugs [isoprenaline hydrochloride, salbutamol sulfate,procaterol hydrochloride, terbutaline sulfate, trimetoquinolhydrochloride, tulobuterol hydrochloride, orciprenaline sulfate,fenoterol hydrobromide, ephedrine hydrochloride, ipratropium bromide,oxyphenonium bromide, flutropium bromide, theophyline, aminophyllin,sodium cromoglycate, tranilast, repirinast, Amlexanox, ibudilast,ketotifen, terfenadine, mequitazine, azelastine, epinastine, ozagrelhydrochloride, pranlkast hydrate, seratrodast, dexamethasone,prednisolone, hydrocortisone, beclomethasone propionate, fluticasonepropionate, beclomethasone dipropionate, procaterol, and the like],therapeutic agents for hypothyroidism [desiccated thyroid (Thyreoid),levothyroxine sodium (Thyroxine S), liothyronine sodium (Thyronine,Thyromin); therapeutic agents for nephrotic syndrome: prednisolone(Predonine), prednisolone sodium succinate (Predonine), sodiummethylprednisolone succinate (Solu-Medrol), betamethasone (Rinderon)],therapeutic drugs for hypertension [(i) sympathetic nerve suppressants[α 2 stimulators (e.g., clonidine, guanabenz, guanfacine, methyldopa,and the like), ganglion blocking drugs (e.g., hexamethonium,trimethaphan, and the like), presynapse blocking agents (e.g.,alseroxylon, dimethylamino reserpinate, Rescinnamine, Reserpine,Syrosingopine, and the like), neuron blocking drugs (e.g., betanidine,guanethidine, and the like), α1 blocking drugs (e.g., bunazosin,doxazosin, prazosin, terazosin, urapidil, and the like), β blockingdrugs (e.g., propranolol, nadolol, timolol, nipradilol, bunitrolol,indenolol, penbutolol, carteolol, carvedilol, pindolol, acebutolol,atenolol, bisoprolol, metoprolol, labetalol, amoslalol, arotinolol, andthe like), and the like, (ii) vasodilator drugs [calcium channelantagonists (e.g., manidipine, nicardipine, nilvadipine, nisoldipine,nitrendipine, benidipine, amlodipine, aranidipine, and the like),phthalazine derivatives (e.g., budralazine, cadralazine, ecarazine,hydralazine, todralazine, and the like), and the like], (iii) ACEinhibitors [alacepril, captopril, cilazapril, Delapril, enalapril,lisinopril, temocapril, trandolapril, quinapril, imidapril, benazepril,perindopril, and the like], (iv) AII antagonists [losartan, candesartan,valsartan, termisartan, irbesartan, forasartan, and the like], (v)diuretics (e.g., the aforementioned diuretics and the like)],therapeutic agents for hypertension: diuretics [e.g, furosemide (Lasix),bumetanide (Luneoron), azosemide (Diart)] hypotensive drugs (e.g., ACEinhibitors, (enalapril maleate (Renivace) and the like) and Caantagonists (manidipine, amlodipine, and the like), α or β receptorblocking drugs and the like], therapeutic agents for hyperlipemia[HMG-CoA reductase inhibitors (e.g., fluvastatin, cerivastatin,atorvastatin, and the like), fibrate drugs (e.g., simfibrate, aluminiumclofibrate, clinofibrate, fenofibrate, and the like), anion exchangeresins (e.g., cholestyramide and the like), nicotinic acid preparations(e.g., nicomol, niceritrol, tocopherol nicotinate, and the like),polyunsaturated fatty acid derivatives (e.g., ethyl icosapenate,polyenephosphatidylcholine, melinamide, and the like), plant sterols(e.g., gamma-oryzanol, soysterol, and the like), elastase, dextransulfate sodium, squalene synthase inhibitors, CEPT inhibitors, ethyl2-chloro-3-[4-(2-methyl-2-phenylpropyloxy)phenyl]propionate (Chemicaland Pharmaceutical Bulletin, 38, 2792-2796 (1990)) and the like], drugsfor treating bone diseases: calcium preparations (e.g., calciumcarbonate and the like), calcitonine preparations, activated vitamin D₃preparations (e.g., alfacarcidol (Alfarol and the like), calcitrol(Rocaltrol) and the like), sex hormones (e.g., estrogen, estradiol andthe like), hormone preparations [e.g., conjugated estrogen (Premarin)and the like], ipriflavone preparations (Osten), vitamin K₂, vitamin K₂preparations [e.g., menatetrenone (Glakay) and the like], bisphosphonicacid preparations (etidronate and the like), prostaglandin E2, fluorinecompounds (e.g., sodium fluoride and the like), bone morphogeneticprotein (BMP), fibroblast growth factor (FGF), platelet derived growthfactor (PDGF), transforming growth factor (TGF-β), insulin-like growthfactors 1 and 2 (IGF-1, -2), parathyroid hormone (PTH), compoundsdescribed in European Patent Application Publication No. EP-A1-376197,EP-A1-460488 and EP-A1-719782 (e.g.(2R,4S)-(−)-N-[4-(diethoxyphosphorylmethyl)phenyl)-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxamide,and the like) and the like), and the like, fat soluble vitamins [(i)vitamin A: vitamin A₁, vitamin A₂, and retinol palmitate, (ii) vitaminD: vitamins D₁, D₂, D₃, D₄, D₅, (iii) vitamin E: α-tocopherol,β-tocopherol, γ-tocopherol, δ-tocopherol, dl-α-tocopherol nicotinate),(iv) vitamin K: vitamins K₁, K₂, K₃, K₄, (v) folic acid (vitamin M), andthe like, vitamin derivatives [derivatives of each type of vitamin,e.g., vitamin D₃ derivatives such as 5,6-trans-cholecalciferol,2,5-hydroxycholecalciferol, 1-α-hydroxycholecalciferol, and the like,vitamin D₂ derivatives such as 5,6-trans-ergocalciferol, and the like],disease modulating antirheumatic drugs and immunosuppressive drugs[e.g., methotrexate, leflunomide, prograf, sulphasalazine,D-penicillamine, oral gold agents], vasopressor drugs [dopamine,dobutamine, denopamine, digitoxin, digoxin, methyldigoxin, lanatoside C,G-strophantin, and the like], myocardiac protection drugs: drugs foropening heart ATP-K, Na—H exchange inhibitors, endothelin antagonists,urotensin antagonists, and the like, drugs for treating cardiacinsufficiency [cardiac restoratives (e.g., digitoxin, digoxin,methyldigoxin, lanatoside C, proscillaridin, and the like), α, βstimulators (e.g., epinephrine, norepinephrine, isoproterenol, dopamine,docarpamine, dobutamine, denopamine, and the like), phosphodiesteraseinhibitors (e.g., amrinone, milrinone, olprinone hydrochloride, and thelike), calcium channel sensitizers (e.g., pimobendan and the like),nitric acid drugs (e.g., nitroglycerin, isosorbide dinitrate, and thelike), ACE inhibitors (e.g., the aforementioned ACE inhibitors and thelike), diuretics (e.g., the aforementioned diuretics and the like),carperitide, ubidecarenone, vesnarinone, aminophylline, and the like],neurotrophic factors, drugs for treating renalinsufficiency/nephropathy, biological preparations [e.g., monoclonalantibodies, (e.g., anti TNF-α antibodies, anti IL-12 antibodies, antiIL-6 antibodies, anti ICAM-I antibodies, anti CD4 antibodies, and thelike), soluble receptors (TNF-α receptors and the like), protein ligands(IL-1 receptor antagonist and the like)], bile acid binding resins[e.g., cholestyramine, colestipol, and the like], drugs for treatingbiliary tract disease: choleratic drugs [e.g., dehydrocholic acid andthe like], cholekinetic agents [e.g., magnesium sulfate and the like]and the like, central nervous system agents: antianxiety drugs, sedativehypnotic drugs, anesthetic drugs, antispasmodic drugs, autonomic drugs,antiparkinsonic drugs and other psychiatric drugs and the like,antitussives and expectorants [ephedrine hydrochloride, noscapinehydrochloride, codeine phosphate, dihydrocodeine phosphate,isoproterenol hydrochloride, ephedrine hydrochloride, methylephedrinhydrochloride, noscapine hydrochloride, alloclamide, chlorphezianol,picoperidamine, cloperastine, protokylol, isoproterenol, salbutamol,terbutaline, oxymethebanol, morphine hydrochloride, dextromethorphanhydrobromide, oxycodone hydrochloride, dimorphan phosphate, tipepidinehibenzate, pentoxyverine citrate, clofedanol hydrochloride, benzonatate,guaifenesin, bromhexine hydrochloride, ambroxol hydrochloride,acetylcysteine, ethylcysteine hydrochloride, carbocysteine, and thelike], sedative drugs [chlorpromazine hydrochloride, atropine sulfate,phenobarbital, barbital, amobarbital, pentobarbital, sodium thiopental,thiamylal sodium, nitrazepam, estazolam, flurazepam, haloxazolam,triazolam, flunitrazepam, bromvalerylurea, chloral hydrate, triclofossodium, and the like], analgesic and antiphlogistic drugs [e.g.,centrally acting analgesics (e.g., morphine, codeine, pentazocine, andthe like), steroids (e.g., prednisolone, dexamethasone, betamethasone,antiphlogistic enzymes (e.g., promercin, lysozyme, proctase, and thelike)], drugs for treating diabetes (sulfonylureas (e.g., tolbutamide,chlorpropamide, glyclopyramide, acetohexamide, tolazamide,glibenclamide, glybuzole, and the like), biguanide agents (e.g.,metformin hydrochloride, buformine hydrochloride, and the like),α-glucosidase inhibitors (e.g., voglibose, acarbose, and the like),drugs for improving insulin resistance (e.g., pioglitazone,troglitazone, and the like), insulin, glucagon, drugs for treatingdiabetic complications (e.g., epalrestat, thioctic acid, and the like),Actos, rosiglitazone, Kinedak, Penfill, Humulin, Euglucon, Glimicron,Daonil, Novolin, Monotard, insulin, Glucobay, Dimelin, Rastinon,Deamelin-S, Iszilin, and the like], cerebral function activation drugs(e.g., Idevenone, vinpocetine, and the like), drugs for treating urinarysystem and male sex organ diseases:[e.g., drugs for treatingprostatomegaly (tamsulosin hydrochloride, prazosin hydrochloride,chlormadinone acetate, and the like)] and the like, non-steroidalantiinflammatory drugs [acetaminophen, phenacetin, ethenzamide,sulpyrine, antipyrine, migrenin, aspirin, mefenamic acid, flufenamicacid, diclofenac sodium, loxoprofen sodium, phenylbutazone,indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen,fenburfen, pranoprofen, floctafenine, epirizole, tiaramidehydrochloride, zaltoprofen, gabexate mesilate, camostat mesilate,urinastatin, colchicine, probenecid, sulfinpyrazone, benzbromarone,allopurinol, sodium aurothiomalate, sodium hyaluronate, sodiumsalicylate, morphine hydrochloride, salicylic acid, atropine,scopolamine, morphine, pethidine, levorphanol, ketoprofen, naproxen,oxymorphone, or salts thereof and the like], drugs for treatingpollakiuria/incontinence [flavoxate hydrochloride and the like],unstable plaque stabilizers [MMP inhibitors, chymase inhibitors, and thelike], antiarrhythmic drugs [sodium channel blocking drugs (e.g.,chinidine, procaineamide, disopyramide, ajmaline, cibenzoline,lidocaine, diphenylhydantoin, mexiletine, propafenone, flecainide,pilsicainide, phenyloin, and the like), β-blocking drugs (e.g.,propranolol, alprenolol, bufetolol, oxprenolol, atenolol, acebuolol,metoprolol, bisoprolol, pindolol, carteolol, arotinolol, and the like),potassium channel blocking drugs (e.g., amiodarone and the like),calcium channel blocking drugs (e.g., verapamil, diltiazem, and thelike) and the like], drugs for treating gynecological diseases: [e.g.,drugs for treating menopausal disorders (conjugated estrogen, estradiol,testosterone enanthnate/estradiol valerate, and the like), drugs fortreating breast tumors (tamoxifen citrate, and the like), drugs fortreating endometriosis/hysteromyoma (leuprorelin acetate, danazol, andthe like)] and the like, anesthetics [a local anesthetics [cocainehydrochloride, procaine hydrochloride, lidocaine, dibucainehydrochloride, tetracaine hydrochloride, mepivacaine hydrochloride,bupivacaine hydrochloride, oxybuprocaine hydrochloride, ethylaminobenzoate, oxethazaine] and the like], b general anesthetics [(i)inhalational anesthetics (e.g., ether, halothane, nitrous oxide,influrane, enflurane), (ii) intravenous anesthetics (e.g., ketaminehydrochloride, droperidol, thiopentone sodium, thiamylal sodium,pentobarbital) and the like]], narcotic antagonists [levallorphan,nalorphine, naloxone, or salts thereof and the like], drugs for treatingchronic heart failure: cardiac stimulants [cardiac glycosides (digoxinand the like), β receptor stimulants (catecholamine preparations such asdenopamine and dobutamine) and PDE inhibitors and the like], diuretics[e.g., furosemide (Lasix), spironolactone (Aldactone), bumetanide(Luneoron), azosemide (Diart) and the like], ACE inhibitors, [e.g.,enalapril maleate (Renivace) and the like], Ca antagonists [e.g.,amlodipine, manidipine, and the like], and β receptor blocking drugs andthe like, immunomodulators [cyclosporin, tacrolimus, gusperimus,azathioprine, antilymphocyte serum, dried sulfonated immunoglobulin,erythropoietin, colony stimulating factor, interleukin, interferon, andthe like], diuretics [thiazide diuretics (benzylhydrochlorothiazide,cyclopenthiazide, ethiazide, hydrochlorothiazide, hydroflumethiazide,methyclothiazide, penflutizide, polythiazide, trichlormethiazide, andthe like), loop diuretics (chlorthalidone, clofenamide, indapamide,mefruside, meticrane, metolazone, tripamide, quinethazone, metolazone,furosemide, mefruside, and the like), potassium sparing diuretics(spironolactone, triamterene, and the like)], and impotence drugs(Viagra, apomorphine, and the like), and the like.

These drugs can be formulated by mixing individually or simultaneouslywith pharmaceutically acceptable carriers, excipients, binders, diluentsor the like, and can be administered orally or non-orally. When thedrugs are formulated individually, they can be mixed with a diluent orthe like at the time of use and then administered, however individuallyformulated preparations may be administered simultaneously or over aperiod of time to the same subject. A kit in which a diluent or the likeis mixed with the individually formulated drugs at the time of use andadministered (e.g. an injection kit which contains ampoules eachcontaining a powdered drug and a diluent for mixing and dissolving twoor more drugs at the time of use, and the like), a kit for administeringindividually formulated preparations simultaneously or over a period oftime to the same subject (e.g. a tablet kit for administering tabletssimultaneously or over a period of time, the kit having two or moretablets each containing a drug and placed in the same or separate bagsand, if necessary, a time table for administering the drugs, and thelike), and the like are also included in the pharmaceutical compositionsof the present invention.

In the event that the aforementioned pharmaceutical compositions areemployed as agents for the prevention and treatment of graft-versus-hostdisease and/or rejection reactions when organs such as the heart,kidney, liver, bone marrow, and the like are transplanted, they can beadministered from 3 days before transplantation, and can be continuouslyadministered after transplantation. The dose per day of the presentpharmaceutical compositions will differ depending on the condition andbody weight of a patient and the method of administration, however withoral administration, about 5 to 1000 mg, preferably about 10 to 600 mg,more preferably about 10 to 300 mg, and in particular about 15 to 150mg, of the active ingredient [Compounds (I), (II), (III), (IV), (Ie)]can be administered per adult patient (body weight 50 kg) once or 2 to 3times per day. In addition, in these cases, other agents for suppressinggraft-versus-host disease and/or rejection reactions during organtransplant may be employed in combination. Specific examples of theagents that are employed to suppress graft-versus-host disease and/orrejection reactions during organ transplant in combination with thecompounds represented by the aforementioned formulas (I), (II), (III),(IV), and (eI) or salts thereof include cyclosporin, tacrolimus,rapamycin, steroids, axathioprine, mycophenolate mofetil, mizoribine,and the like. In the event that these drugs are employed in combination,the dosage of each drug can be suitably adjusted when one drug has animpact on the metabolism of another drug, however the dosage that isgenerally employed is that when each drug is administered alone.

The daily dosage of the compounds represented by the aforementionedformulas (I), (II), (III), (IV), and (eI) or salts thereof that areemployed for diseases other than the suppression of graft-versus-hostdisease and/or rejection reactions during organ transplant will differdepending on the type of disease, the condition and body weight of apatient, and the method of administration, however with oraladministration, about 5 to 1000 mg, preferably about 10 to 600 mg, morepreferably about 10 to 300 mg, and in particular about 15 to 150 mg, ofthe active ingredient [Compounds (I), (II), (III), (IV), (Ie)] can beadministered per adult patient (body weight 50 kg) once or 2 to 3 timesper day. In addition, in the event that other drugs are used incombination, the dosage of the other drugs can, for example, be suitablyselected in a range between about 1/200 to 1/2 times or greater, andabout 2 to 3 times or less, than the normal dosage. Furthermore, in theevent that two or more types of drugs are employed in combination, thedosage of each drug can be suitably adjusted when one drug has an impacton the metabolism of another drug, however the dosage that is generallyemployed is that when each drug is administered alone.

The following working examples, reference examples, experimentalexamples, and formulation examples are illustrated below to describe thepresent invention in further detail. However, these are merely examples,and do not limit the present invention in any way.

The following gene manipulation method is carried out in accordance withmethods described in the textbook (Maniatis et al., Molecular Cloning,Cold Spring Harbor. Laboratory, 1989) or the method described in theprotocols that accompany the reagents.

In the reference examples and working examples below, silica gel 60(Merck Corp., 70 to 230 or 230 to 400 mesh) was used as packing forcolumn chromatography unless otherwise noted. ¹H NMR spectra weremeasured using tetramethylsilane as an internal reference with a Gemini200 spectrometer (Varian, 200 MHz).

REFERENCE EXAMPLE 1-1 t-Butyl 4-(2-ethoxy-2-oxoethylidene)-1-piperidinecarboxylate

To a solution of ethyl diethylphosphoryl acetate (28.3 g) intetrahydrofuran (200 ml) was added 60% sodium hydride (4.82 g) under icecooling and the mixture was stirred for 30 minutes, and then a solutionof N-butoyxcarbonyl-4-piperidone (20 g) in tetrahydrofuran (200 ml) wasadded dropwise thereto. The mixture was stirred for 22 hours at roomtemperature. After the completion of the reaction, water (200 ml) wasadded and extraction was carried out with ethyl acetate. After theextract was washed with saturated aqueous sodium chloride solution anddried over anhydrous magnesium sulfate, the concentrated residueobtained was then purified using silica gel column chromatography andeluted with hexane/ethyl acetate (6/1) to obtain the title compound(27.3 g, 100%) as a colorless powder.

¹H NMR (CDCl₃) δ 1.28 (3H, t, J=7.4 Hz), 1.47 (9H, s), 2.24-2.33 (2H,m), 2.90-2.98 (2H, m), 3.43-3.55 (4H, m), 4.16 (2H, q, J=7.4 Hz),5.70-5.73 (1H, m).

REFERENCE EXAMPLE 1-2 [1-(Methylsulfonyl)-4-piperidylidene]ethyl acetate

The compound (10 g) obtained in Reference Example 1-1 was dissolved inmethanol (100 ml), and 4N hydrochloric acid-ethyl acetate (20 ml) andtrifluoroacetic acid (2.5 ml) were added and the mixture was stirred for3 hours. The solvent was evaporated, and the residue obtained was washedwith ethyl acetate to obtain a colorless powder (6.64 g).

The colorless powder (6.64 g) obtained were added to tetrahydrofuran(100 ml) and triethylamine (9.9 ml), mesyl chloride (3 ml) was addeddropwise with ice cooling, and the mixture was stirred at roomtemperature for 1 hour. After completion of the reaction, water (100 ml)was added and the mixture was extracted with ethyl acetate. After theextract was washed with saturated aqueous sodium chloride solution anddried over anhydrous magnesium sulfate, the concentrated residueobtained was then purified using silica gel column chromatography andeluted with hexane/ethyl acetate (1/1) to obtain the title compound(6.18 g, 68%) as a colorless powder.

¹H NMR (CDCl₃) δ 1.29 (3H, t, J=7.0 Hz), 2.39-2.48 (2H, m), 2.80 (3H,s), 2.99-3.14 (2H, m), 3.27-3.40 (4H, m), 4.17 (2H, q, J=7.0 Hz),5.37-5.77 (1H, m).

REFERENCE EXAMPLE 1-3 [1-(Methylsulfonyl)-4-piperidinyl]ethyl acetate

The compound obtained in Reference Example 1-2 and 10% palladium-carbon(0.3 g) were added to ethanol (50 ml) and the mixture was stirred underhydrogen for 5 hours. After the reaction was completed, insolublematerials were filtered off with celite, the filtrate was concentratedand the residue obtained was purified using silica gel columnchromatography, and the title compound (1.62 g, 100%) as a colorlessoily material was obtained from the fraction eluted with hexane/ethylacetate (1/1).

¹H NMR (CDCl₃) δ 1.26 (3H, t, J=7.0 Hz), 1.33-1.48 (2H, m), 1.78-2.02(3H, m), 2.28 (2H, d, J=6.6 Hz), 2.68 (2H, dt, J=2.4, 12.0 Hz), 2.77(3H, s), 3.74-3.85 (2H, m), 4.15 (2H, q, J=7.0 Hz).

REFERENCE EXAMPLE 1-4 [1-(Methylsulfonyl)-4-piperidinyl]acetate

The compound (1.61 g) obtained in Reference Example 1-3 was dissolved inmethanol (30 ml), and 8N sodium hydroxide solution (30 ml) and water (3ml) were added and the mixture was stirred for 8 hours. After thereaction was completed, 6N hydrochloric acid (8 ml) was added and theorganic solvent was evaporated. The aqueous layer was extracted withethyl acetate, dried over anhydrous magnesium sulfate, and concentratedto obtain the title compound (1.29 g, 90%) as a colorless powder.

¹H NMR (CDCl₃) δ 1.29-1.54 (2H, m), 1.80-2.03 (3H, m), 2.35 (2H, d,J=.6.6 Hz), 2.69 (2H, dt, J=2.2, 12.0 Hz), 2,78 (3H, s), 3.75-3.88 (2H,m).

REFERENCE EXAMPLE 1-5 [1-(Methylsulfonyl)-4-piperidinyl]acetyl chloride

The compound (1.29 g) obtained in Reference Example 1-4 was dissolved indichloromethane (30 ml), and N,N-dimethyl formamide (0.045 ml) andoxalyl chloride (0.76 ml) were added and the mixture was stirred for 5hours and concentrated to obtain the title compound (1.4 g, 100%) as abrown powder.

REFERENCE EXAMPLE 2-1 4-[(1-Acetyl-4-piperidinyl)methyl]benzenesulphonylchloride

A solution of 1-acetyl-4-benzylpiperidine (60.00 g) in dichloromethane(100 ml) was added dropwise over 1 hour to chlorosulfonic acid (92 ml)at 0° C. with stirring, and the mixture was then stirred for 30 minutesat 0° C. and for 1.5 hours at room temperature. The reaction mixture waspoured into ice water (1 L), and extracted with dichloromethane (500 ml,250 ml). The organic layer was washed with 5% sodium carbonate solution(500 ml×2) and saturated saline solution (250 ml). The organic layer wasdried over anhydrous magnesium sulfate, filtered and concentrated underreduced pressure. The residue was subjected to column chromatography(silica gel 250 g, ethyl acetate), and the target fraction wasconcentrated under reduced pressure to obtain the title compound (54.22g) as a white solid.

¹H NMR (CDCl₃) δ 1.05-1.35 (2H, m), 1.6-1.95 (3H, m), 2.09 (3H, s),2.35-2.65 (1H, m), 2.68 (2H, d, J=6.6 Hz), 2.85-3.15 (1H, m), 3.7-3.9(1H, m), 4.5-4.75 (1H, m), 7.39 (2H, d, J=8.4 Hz), 7.97 (2H, d, J=8.4Hz).

REFERENCE EXAMPLE 2-2 1-Acetyl-4-[4-(methylsulfonyl)benzyl]piperidine

4-[(1-Acetyl-4-piperidinyl)methyl]benzenesulphonyl chloride (11.46 g)was gradually added to a solution (40 ml) of sodium sulfite (4.57 g) andsodium bicarbonate (6.10 g) in water (40 ml) at 75° C. with stirring,and the mixture was stirred for 1 hour at 75° C. Chloroacetic acid (5.14g) and 50% sodium hydroxide solution in water (4.4 ml) were added, andthe mixture was heated under reflux and stirred for 20 hours. To thiswas added 1N hydrochloric acid (20 ml) at 0° C., and then the mixturewas extracted with ethyl acetate (60 ml, 30 ml). The organic layer waswashed with saturated saline solution (10 ml×2), and dried overanhydrous magnesium sulfate. The mixture was filtered, and concentratedunder reduced pressure. The residue was subjected to columnchromatography (silica gel 150 g, ethyl acetate/methanol=1/0→9/1), andthe target fraction was concentrated under reduced pressure to obtainthe title compound (8.76 g) as a colorless oily material.

¹H NMR (CDCl₃) δ 1.05-1.35 (2H, m), 1.55-1.95 (3H, m), 2.08 (3H, s),2.4-2.6 (1H, m), 2.66 (2H, d, J=7.4 Hz), 2.9-3.1 (1H, m), 3.06 (3H, s),3.7-3.9 (1H, m), 4.55-4.7 (1H, m), 7.34 (2H, d, J=8.4 Hz), 7.87 (2H, d,J=8.4 Hz).

REFERENCE EXAMPLE 2-3 4-[4-(Methylsulfonyl)benzyl]piperidinehydrochloride

A mixture of 1-acetyl-4-[4-(methylsulfonyl)benzyl]piperidine (8.76 g)and concentrated hydrochloric acid (100 ml) was heated under reflux, andstirred for 4 hours. The reaction mixture was concentrated under reducedpressure, 2-propanol (100 ml) was added, and the mixture wasconcentrated under reduced pressure. 2-Propanol (50 ml) was added to theresidue, and the mixture was heated under reflux, and stirred for 30minutes. This was cooled to room temperature, the precipitate wasfiltered off, the precipitate was washed with 2-propanol, and driedunder reduced pressure to obtain the title compound (7.51 g) as a whitesolid.

¹H NMR (CD₃OD) δ 1.3-1.6 (2H, m), 1.75-2.1 (3H, m), 2.75 (2H, d, J=7.0Hz), 2.8-3.05 (2H, m), 3.10 (3H, s), 3.25-3.45 (2H, m), 7.49 (2H, d,J=8.1 Hz), 7.89 (2H, d, J=8.1 Hz).

REFERENCE EXAMPLE 2-4 4-[4-(Methylsulfonyl)benzyl]piperidine

4-[4-(Methylsulfonyl)benzyl]piperidine hydrochloride (1 g) was dissolvedin water (10 ml), 1N sodium hydroxide solution (5 ml) was added at 0°C., the mixture was stirred for 5 minutes, and then the aqueous layerwas extracted with dichloromethane (10 ml×3). The organic layer wasdried over potassium carbonate, and then filtered and concentrated underreduced pressure. Diisoproylether (10 ml) was added to the residue, andthe precipitate was filtered off. The precipitate was washed withdiisopropylether, and then was dried at reduced pressure to obtain thetitle compound (712 mg) as a white solid.

¹H NMR (CDCl₃) δ 1.07-1.27 (2H, m), 1.50-1.73 (3H, m), 2.48-2.61 (2H,m), 2.62 (2H, d, J=6.6 Hz), 3.03-3.08 (2H, m), 3.05 (3H, s), 7.34 (2H,d, J=8.4 Hz), 7.85 (2H, d, J=8.4 Hz).

REFERENCE EXAMPLE 2-5N-(3-{4-[4-(4-Methylsulfonyl)benzyl]-1-piperidinyl}propyl)anilinedihydrochloride

A solution of 90% acrolein (3.7 ml) in tetrahydrofuran (10 ml) was addeddropwise to a solution of 4-[4-(methylsulfonyl)benzyl]piperidine (12.6g) and DBU (0.074 ml) in tetrahydrofuran (90 ml) with stirring at −28°C., and the mixture was stirred for 1 hour from −20° C. to −10° C.3,4-Dichloroaniline (8.07 g) and triacetoxy sodium borohydride (21.1 g)were sequentially added at −10° C., and then this mixture was raised toroom temperature while stirring for 7 hours. Diethyl ether (150 ml) and1N sodium hydroxide solution (240 ml) were added, and the mixture wasstirred for 30 minutes. The separated aqueous layer was extracted twicewith a mixture of diethyl ether and tetrahydrofuran (100 ml+50 ml). Thecombined organic layer was dried over anhydrous magnesium sulfate, andthen concentrated under reduced pressure. The residue was purified withsilica gel column chromatography and a light brown oily material (15 g,66%) was obtained from the fraction eluted with methanol/ethyl acetate(1/4). This compound was dissolved in 2-propanol (100 ml), a 4N hydrogenchloride ethyl acetate solution (100 ml) was added with stirring, andthe precipitate was filtered off. The precipitate was washed with ethylacetate, and dried at reduced pressure to obtain the title compound(16.3 g, 94%) as a light brown powder.

¹H NMR(CD₃OD) δ 1.59-2.35 (7H, m), 2.75 (2H, d, J=6.4 Hz), 2.86-3.05(2H, m), 3.13 (3H, s), 3.22 (2H, t, J=7.4 Hz), 3.48 (2H, t, J=8.0 Hz),3.59-3.68 (2H, m), 6.63-6.75 (3H, m), 7.10-7.25 (2H, m), 7.50 (2H, d,J=8.2 Hz), 7.90 (2H, d, J=8.2 Hz).

REFERENCE EXAMPLE 3-1 1-Acetyl-4-[4-(isopropylsulfanyl)benzyl]piperidine

The compound obtained in Reference Example 2-1 (16.9 g) and powderedzinc (36.7 g) were added to a mixture of concentrated sulfuric acid (36ml) and water (200 ml) under ice cooling, and the reaction mixture wasstirred for 5 hours at 60° C. After cooling to room temperature, thefiltrate was extracted with dichloromethane (200 ml×2), the organiclayer was dried over anhydrous magnesium sulfate and then concentratedunder reduced pressure, and 1-acetyl-4-(4-mercaptobenzyl)piperidine wasobtained as a colorless oily material.

The aforementioned compound was dissolved in N,N-dimethylformamide (300ml), and 2-propyl iodide (7.3 ml) and potassium carbonate (8.86 g) wereadded and the mixture was stirred for 20 hours. After the solvent wasevaporated, ethyl acetate (200 ml) and water (200 ml) were added to theresidue obtained and the mixture was stirred for 10 minutes. Theseparated organic layer was washed with saturated saline solution, andthen the concentrated. The residue obtained was purified with silica gelcolumn chromatography, and the title compound (10.2 g, 66%) as acolorless oily material was obtained from the fraction eluted with ethylacetate.

¹H NMR (CDCl₃) δ1.02-1.30 (2H, m), 1.29 (6H, d, J=6.6 Hz), 1.60-1.82(3H, m), 2.07 (3H, s), 2.40-2.58 (3H, m), 2.90-3.05 (1H, m), 3.25-3.42(1H, m), 3.70-3.85 (1H, m), 4.55-4.65 (1H, m), 7.06 (2H, d, J=8.0 Hz),7.33 (2H, d, J=8.0 Hz).

REFERENCE EXAMPLE 3-2 1-Acetyl-4-[4-(isopropylsulfonyl)benzyl]piperidine

M-Chloroperbenzoic acid was added under ice cooling to a solution of thecompound (1.06 g) obtained in Reference Example 3-1 in dichloromethane(30 ml), and the mixture was stirred at room temperature for 3 hours.The reaction mixture was diluted with dichloromethane (30 ml), theorganic layer was washed twice with 5% sodium thiosulfate solution and asaturated sodium bicarbonate solution, and then washed with a saturatedsodium bicarbonate solution and a saturated saline solution. Afterdrying over anhydrous magnesium sulfate, the residue was concentratedunder reduced pressure and subjected to silica gel column chromatography(ethyl acetate/methanol=10/1). The target fraction was concentratedunder reduced pressure to obtain the title compound (1.12 g, 95%) as acolorless oily material.

¹H NMR (CDCl₃) δ1.03-1.40 (2H, m), 1.29 (6H, d, J=6.8 Hz), 1.53-2.00(3H, m), 2.07 (3H, s), 2.40-2.70 (3H, m), 2.82-3.05 (1H, m), 3.10-3.25(1H, m), 3.70-3.85 (1H, m), 4.55-4.70 (1H, m), 7.32 (2H, d, J=8.2 Hz),7.80 (2H, d, J=8.2 Hz).

REFERENCE EXAMPLE 3-3 4-[4-(Isopropylsulfonyl)benzyl]piperidine

10N Hydrochloric acid (100 ml) was added to the compound (11.4 g)obtained in Reference Example 3-2, and heated under reflux for 6 hours.After the reaction was completed, an 8N sodium hydroxide solution (200ml) was added dropwise under ice cooling, and the mixture was extractedwith dicyclomethane (200 ml). The reaction mixture was dried overanhydrous magnesium sulfate and concentration under reduced pressure toobtain the title compound (9.56 g, 96%) as a colorless powder.

¹H NMR (CDCl₃) δ1.07-1.25 (2H, m), 1.30 (6H, d, J=7.0 Hz), 1.55-1.78(3H, m), 2.55 (2H, ddd, J=2.6, 12.0, 12.0 Hz), 2.62 (2H, d, J=6.8 Hz),3.00-3.30 (3H, m), 7.33 (2H, d, J=8.4 Hz), 7.78 (2H, d, J=8.4 Hz).

REFERENCE EXAMPLE 3-4N-(3-{4-[4-(4-Isopropylsulfonyl)benzyl]-1-piperidinyl}propyl)anilinedihydrochloride

The compound obtained in Reference Example 3-3 was employed, and thetitle compound was synthesized with the same method as that of ReferenceExample 2-5. Yield 36%

¹H NMR(CDCl₃; free) δ 1.18-1.95 (9H, m), 1.30 (6H, d, J=7.0 Hz), 2.44(2H, t, J=6.6 Hz), 2.66 (2H, d, J=6.2 Hz), 2.85-3.00 (2H, m), 3.05-3.27(3H, m), 6.39 (1H, dd, J=2.6, 8.4 Hz), 6.62 (1H, d, J=2.6 Hz), 7.16 (1H,d, J=8.4 Hz), 7.34 (2H, d, J=8.4 Hz), 7.80 (2H, d, J=8.4 Hz).

REFERENCE EXAMPLE 4-14-Hydroxy-1-(methylsulfonyl)-4-piperidinecarbonitrile

A solution of 1-(methylsulfonyl)-4-piperidinone (synthesized by themethod disclosed in U.S. Pat. No. 6,051,582)(1 g, 5.64 mmol) andpotassium cyanide (551 mg, 8.5 mmol) in acetic acid (6 ml) was stirredat room temperature for 18 hours. The reaction mixture was concentratedunder reduced pressure, water (20 ml) was added to the residue obtained,and the mixture was extracted with ethyl acetate (20 ml×2). The organiclayer was washed with aqueous 10% sodium bicarbonate (20 ml×2) andsaturated saline solution (20 ml), and after drying over anhydroussodium sulfate, the solvent was evaporated under reduced pressure. Theresidue obtained was purified by flash column chromatography (silica gel25 g, ethyl acetate/hexane=1/5→1/1) to obtain the title compound (528.1mg, 46%) as colorless powder crystals.

¹H NMR (CDCl₃) δ1.97-2.10 (2H, m), 2.18-2.28 (2H, m), 2.74 (1H, s), 2.83(3H, s), 3.29-3.38 (2H, m), 3.49-3.63 (2H, m)

REFERENCE EXAMPLE 4-24-Hydroxy-1-(methylsulfonyl)-4-piperidinecarboxylic acid

Concentrated hydrochloric acid (2 ml) was added to the compound (528 mg,2.59 mmol) obtained in Reference Example 4-1, and the mixture wasstirred at room temperature for 12 hours. The reaction mixture wasconcentrated under reduced pressure, the residue obtained was subjectedto azeotropy with toluene, and the resulting solid was dried underreduced pressure to obtain the title compound (580 g, 100%) as colorlesspowder crystals.

¹H NMR (CD₃OD) δ1.64-1.95 (2H, m), 2.02-2.17 (2H, m), 2.85 (3H, s),3.05-3.19 (2H, m), 3.53-3.65 (2H, m)

REFERENCE EXAMPLE 5N-(3,4-Dichlorophenyl)-N-(3-{4-[4-(methylsulfonyl)benzyl]-1-piperidinyl}propyl)-2-[1-(methylsulfonyl)-4-piperidinyl]acetamide

The compound (0.6 g) obtained in Reference Example 1-5 was divided into3 portions and added at 5 minute intervals to a mixture of the compoundobtained in Reference Example 2-5 (0.88 g) and triethylamine (0.93 ml)in acetomitrile (15 ml) under ice cooling, and the reaction mixture wasstirred for 16 hours at 50° C. After the reaction was completed, thereaction mixture was diluted with ethyl acetate at room temperature, andthe diluent was washed with water, saturated sodium bicarbonatesolution, and saturated saline solution. After drying over anhydrousmagnesium sulfate, the concentrated residue obtained was subjected tosilica gel column chromatography (Chromatorex NH), the oily materialobtained from the fraction eluted with ethyl acetate was furtherpurified with silica gel column chromatography, and a colorlessamorphous material (0.699 g, 64%) was obtained from the fraction elutedwith ethyl acetate/methanol/triethylamine (90/30/12).

¹H NMR (CDCl₃) δ1.10-1.40 (2H, m), 1.52-2.02 (14H, m), 2.82 (2H, t,J=7.2 Hz), 2.55-2.71 (4H, m), 2.75 (3H, s), 2.75-2.88 (2H, m), 3.05 (3H,s), 3.62-3.81 (4H, m), 6.99 (1H, dd, J=2,2, 8.4 Hz), 7.26 (1H, d, J=2.2Hz), 7.32 (2H, d, J=8.4 Hz), 7.51 (1H, d, J=8.4 Hz), 7.84 (2H, d, J=8.4Hz).

REFERENCE EXAMPLE 6N-(3,4-Dichlorophenyl)-N-(3-{4-[4-(isopropylsulfonyl)benzyl]-1-piperidinyl}propyl)-2-[1-(methylsulfonyl)-4-piperidinyl]acetamide

The compound (0.29 g) obtained in Reference Example 1-5 was divided into2 portions and added to a solution of the compound obtained in ReferenceExample 3-4 (0.292 g) and triethylamine (0.085 ml) in dichloromethane (5ml) under ice cooling, and the mixture was stirred for 1.5 hours at roomtemperature. The compound (0.145 g) obtained in Reference Example 1-5and triethylamine (0.085 ml) were added again, and the mixture wasstirred for 1 hour at room temperature. Saturated sodium bicarbonatesolution (10 ml) was added to the reaction mixture, and the organicsolvent was evaporated. After the aqueous layer was extracted with ethylacetate (50 ml), and the extract was washed with saturated sodiumbicarbonate (30 ml×2) and saturated saline solution (30 ml), dried overanhydrous magnesium sulfate. The concentrated residue obtained wassubjected to silica gel column chromatography (Chromatorex NH), the oilymaterial obtained from the fraction eluted with ethyl acetate wasfurther purified with silica gel column chromatography, and a colorlessamorphous material (0.231 g, 56%) was obtained from the fraction elutedwith ethyl acetate.

¹H NMR (CDCl₃) δ1.05-1.40 (2H, m), 1.30 (6H, d, J=6.8 Hz), 1.45-2.10(14H, m), 2.29 (2H, t, J=7.3 Hz), 2.55-2.73 (4H, m), 2.75 (3H, s),2.75-2.89 (2H, m), 3.10-3.28 (1H, m), 3.62-3.85 (4H, m), 7.00 (1H, dd,J=2.6, 8.4 Hz), 7.27 (1H, d, J=2.6 Hz), 7.32 (2H, d, J=8.4 Hz), 7.52(1H, d, J=8.4 Hz), 7.78 (2H, d, J=8.4 Hz).

REFERENCE EXAMPLE 73-(1-Acetyl-4-piperidinyl-N-(3,4-dichlorophenyl)-N-(3-{4-[4-(methylsulfonyl)benzyl]-1-piperidinyl}propyl)-propanamide

3-(1-Acetyl-4-piperidinyl)proprionic acid (0.597 g),N,N-dimethylformamide (0.044 ml) and oxalyl chloride (0.39 ml) weremixed and stirred for 1.5 hours. The reaction mixture was concentratedto obtain a yellow oily material.

A solution of the aforementioned oily material in dichloromethane (15ml) was added to a solution of the compound (0.792 g) obtained inReference Example 2-5 and triethylamine (0.84 ml) in dichloromethane (5ml) under ice cooling, and the mixture was stirred for 15 hours at roomtemperature. After the solvent was evaporated, ethyl acetate and waterwere added to the residue obtained, and the separated organic layer waswashed with saturated saline solution, and the organic layer was driedover anhydrous magnesium sulfate. The concentrated residue obtained wassubjected to silica gel column chromatography (Chromatorex NH), and acolorless oily material (54 mg, 6%) was obtained from the fractioneluted with ethyl acetate.

¹H NMR (CDCl₃) δ0.88-1.91 (15H, m), 1.95-2.12 (2H, m), 2.06 (3H, s),2.20-2.55 (4H, m), 2.62 (2H, d, J=6.6 Hz), 2.77-3.05 (3H, m), 3.05 (3H,s), 3.62-3.83 (3H, m), 4.48-4.61 (1H, m), 7.02 (1H, dd, J=2.4, 8.6 Hz),7.30 (1H, d, J=2.4 Hz), 7.33 (2H, d, J=8.3 Hz), 7.51 (1H, d, J=8.6 Hz),7.85 (2H, d, J=8.6 Hz).

REFERENCE EXAMPLE 8N-(3,4-Dichlorophenyl)-4-hydroxy-1-(methylsulfonyl)-N-(3-{4-[4-(methylsulfonyl)benzyl]-1-piperidinyl}propyl)-4-piperidinecarboxyamide

Oxalyl chloride (0.325 ml, 3.74 mmol) was added dropwise to a solutionof the compound obtained in Reference Example 4-2 (555 mg, 2.49 mmol)and N,N-dimethylformamide (0.0193 ml, 0.249 mmol) in methylene chloride(10 ml), and the mixture was stirred for 1 hour at room temperature, andthen concentrated under reduced pressure. A solution of the residueobtained in methylene chloride (5 ml) was added dropwise at 0° C. to asolution of the compound obtained in Reference Example 2-5 (439 mg, 0.83mmol) and triethylamine (1.39 ml, 9.96 mmol) in methylene chloride (10ml), and the mixture was stirred for two hours at the same temperatureand was stirred for 2 hours at room temperature. After the reactionmixture was washed with water (20 ml) and saturated saline solution (20ml), and dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue obtained was purified bycolumn chromatography [Chromatorex NH-DM-1020 (Fuji Sylysia Chemical);30 g, ethyl acetate/hexane=1/1→3/1] to obtain the title compound (34.4mg, 6.3%) as colorless powder crystals.

¹H NMR (CDCl₃) δ1.22-2.20 (13H, m), 2.33-2.40 (2H, m), 2.64 (2H, d,J=6.0 Hz), 2.78 (3H, s), 2.87-2.93 (2H, m), 3.06 (3H, s), 3.10-3.20 (2H,m), 3.56-3.61 (2H, m), 4.00-4.17 (2H, m), 7.06 (1H, dd, J=8.0 Hz, 2.6Hz), 7.32 (1H, d, J=2.6 Hz), 7.35 (2H, d, J=8.0 Hz), 7.49 (1H, d, J=8.0Hz), 7.86 (2H, d, J=8.0 Hz).

EXPERIMENTAL EXAMPLE Effects of a Compound with Respect to a Mouse SkinGraft Rejection Model

Abdominal skin (10 mm square) of a donor mouse B6-CH-2^(bm12) wasgrafted onto a recipient mouse (B6/129), and 10 mg/kg of an experimentalcompound(N,N-dimethyl-N-(4-[[[2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]carbonyl]amino]benzyl]tetrahydro-2H-pyran-4-ammoniumchloride) was administered subdermally thereto once a day from the dayof grafting. When the presence or absence of graft rejection wasobserved visually over time, the number of days of skin graft life forthe control group and the group that was administered the compound wererespectively 13.0±2.8 days (n=6) and 19.6±4.4 days (n=7), and thus asignificant (P<0.05 vs. control, log-rank test) graft rejectionsuppression effect was observed with the administration of the compound.

EXAMPLE 1 Capsule

(1) 1-Acetyl-N-(3-{4-[4-(aminocarbonyl)benzyl]-  40 mg1-piperidinyl}propyl)-N-(3-chloro-4-methylphenyl)-4- piperidinecarboxamide (2) Lactose  70 mg (3) Fine crystalline cellulose  9 mg (4)Magnesium stearate  2 mg One capsule 120 mg

(1), (2) and (3) and ½ of (4) are mixed together, and then granulated.To the granules is added the reminder of (4), and the whole is filledinto a gelatin capsule.

EXAMPLE 2 Tablet

(1) N-(3,4-Dichlorophenyl)-N-  40 mg (3-{4-[4-(methylsulfonyl)benzyl]-1-piperidinyl}propyl)-2-[1-(methylsulfonyl)- 4-piperidinyl]acetamide (2)Lactose  58 mg (3) Corn starch  18 mg (4) Fine crystalline cellulose 3.5 mg (5) Magnesium stearate  0.5 mg One tablet 120 mg

(1), (2), (3), ⅔ of (4) and ½ of (5) are mixed together, and thengranulated. To the granules are added the reminders of (4) and (5),followed by subjecting the mixture to compression molding to prepare atablet.

EXAMPLE 3 Capsules

(1) N-[3-(4-benzyl-1-piperidinyl)propyl]-  40 mg N-phenyl-N′-phenylureahydrochloride (2) Lactose  70 mg (3) Fine crystalline cellulose  9 mg(4) Magnesium stearate  1 mg One capsule 120 mg

(1), (2) and (3) and ½ of (4) are mixed together, and then granulated.To the granules is added the reminder of (4), and the whole is filledinto a gelatin capsule.

EXAMPLE 4 Tablet

(1) N-[3-(4-benzyl-1-piperidinyl)propyl]-  40 mgN′-(4-chlorophenyl)-N-(4-methylphenyl)urea hydrochloride (2) Lactose  58mg (3) Corn starch  18 mg (4) Fine crystalline cellulose  3.5 mg (5)Magnesium stearate  0.5 mg One tablet 120 mg

(1), (2), (3), ⅔ of (4) and ½ of (5) are mixed together, and thengranulated. To the granules are added the reminders of (4) and (5),followed by subjecting the mixture to compression molding to prepare atablet.

INDUSTRIAL APPLICABILITY

Compounds represented by the formulas (I), (II), (III), (IV) and (eI)employed in the present invention or salts thereof have a CCR antagonisteffect, and particularly a CCR 5 antagonist effect, a CXCR4 antagonisteffect, a CXCR3 antagonist effect, a CCR2 antagonist effect, and a CCR3antagonist effect, and thus can be effectively used as an agent for theprevention and treatment of graft-versus-host disease and/or rejectionreactions, and as an agent for the prevention and treatment of chronicrheumatoid arthritis, autoimmune diseases, allergic disorders, ischemicbrain cell injury, myocardial infarction, chronic nephritis, andarteriosclerosis.

1. An agent for the prevention or treatment of graft-versus host diseaseand/or rejection reactions during organ or bone marrow transplantationwhich comprises a compound having a CCR antagonistic effect representedby the formula:

wherein R^(a1) is a hydrogen atom, a hydrocarbon group which may besubstituted, a non-aromatic heterocyclic group which may be substituted,R^(a2) is a hydrocarbon group which may be substituted, a non-aromaticheterocyclic group which may be substituted, or R^(a1) and R^(a2) maycombine with each other together with A^(a) to form a heterocyclic groupwhich may be substituted, A^(a) is N or N⁺—R^(a5).Y^(a−) (R^(a5) is ahydrocarbon group, Y^(a−) is a counter anion), R^(a3) is a cyclichydrocarbon group which may be substituted or a heterocyclic group whichmay be substituted, na is 0 or 1, R^(a4) is a hydrogen atom, ahydrocarbon group which may be substituted, a heterocyclic group whichmay be substituted, an alkoxy group which may be substituted, an aryloxygroup which may be substituted, or an amino group which may besubstituted, E^(a) is a divalent aliphatic hydrocarbon group which maybe substituted by a group other than an oxo group, G^(a1) is a bond, COor SO₂, G^(a2) is CO, SO₂, NHCO, CONH or OCO, J^(a) is methine or anitrogen atom, and each of Q^(a) and R^(a) is a bond or a divalent C₁₋₃aliphatic hydrocarbon which may be substituted, with the proviso thatJ^(a) is methine when G^(a2) is OCO, one of Q^(a) and R^(a) is not abond when the other is a bond, and each of Q^(a) and R^(a) is notsubstituted by an oxo group when G^(a1) is a bond, the formula:

wherein R^(b1) is a hydrocarbon group which may be substituted; R^(b2)is a cyclic hydrocarbon group which may be substituted or a heterocyclicgroup which may be substituted; R^(b3) is a halogen atom, a carbamoylgroup which may be substituted, a sulfamoyl group which may besubstituted, an acyl group derived from a sulfonic acid, a C₁₋₄ alkylgroup which may be substituted, a C₁₋₄ alkoxy group which may besubstituted, an amino group which may be substituted, a nitro group or acyano group; R^(b4) is a hydrogen atom or a hydroxy group; nb is aninteger of 0 or 1; pb is an integer of 0 or 1 to 4, the formula:

wherein R^(c1) is a hydrocarbon group, R^(c2) is a hydrocarbon grouphaving 2 or more carbon atoms, or R^(c1) and R^(c2) may be boundtogether with the adjacent nitrogen atom to form a ring which may have asubstituent or substituents, R^(c3) is a hydrocarbon group which mayhave a substituent or substituents or a heterocyclic group which mayhave a substituent or substituents, R^(c4) is a hydrogen atom, ahydrocarbon group which may have a substituent or substituents or aheterocyclic group which may have a substituent or substituents, E^(c)is a divalent aliphatic hydrocarbon group which may have a substituentor substituents other than an oxo group, G^(c) is CO or SO₂, J^(c) is anitrogen atom or a methine group which may have a substituent orsubstituents, and Q^(c) and R^(c) are each a bond or a divalentaliphatic C₁₋₃ hydrocarbon group which may have a substituent orsubstituents, the formula:

wherein A^(d) is a group represented by the formula:

wherein, R^(d3) is (1) a hydrocarbon group which may be substituted, (2)a C₁₋₄ alkoxy group which may be substituted or (3) an amino group whichmay be substituted; X^(d) is a bond, —SO₂— or —CO—; nd is an integer of1 to 3; md is 0 or an integer of 1 to 3; R^(d4) and R^(d5) are the sameor different and each of which is a hydrogen atom or a C₁₋₆ alkyl group;R^(d6) is a hydroxyl group, a C₁₋₆ alkyl group or a C₂₋₆ alkenyl group;rd is an integer of 2 to 4; B^(d) is a bond, —CH₂—, —SO₂—, —SO—, —S—,—O—, —CO—, —NR^(da)—SO₂— or —NR^(da)—CO— (wherein, R^(da) is a hydrogenatom, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group or a C₃₋₈ cycloalkylgroup); each of pd and qd is 0 or an integer of 1 to 4; R^(d1) is ahalogen atom, a C₁₋₆ alkyl group, a C₂₋₄ alkenyl group, a C₁₋₄ alkanoylgroup, a C₁₋₄ alkoxy group, a cyano group, a trifloromethyl group, anitro group, a hydroxyl group, an amino group or an amidino group;R^(d2) is 1) a halogen, 2) a C₁₋₆ alkyl which may be substituted by ahalogen or a C₁₋₄ alkoxy, 3) a C₁₋₄ alkoxy which may be substituted by ahalogen or a C₁₋₄ alkoxy, 4) nitro, 5) cyano, 6) hydroxyl, 7) a C₁₋₄alkanoylamino, 8) SO₂NR^(db)R^(dc), 9) SO₂R^(dd), 10) CONR^(db)R^(dc),11) NR^(db)R^(dc) or 12) NR^(da)—SO₂R^(dd) (wherein, R^(da) has themeaning given above, and R^(db) and R^(dc) may be the same or different,and are (1) a hydrogen atom, (2) a C₁₋₆ alkyl group which may besubstituted by a halogen or a C₁₋₄ alkoxy, or (3) a C₃₋₈ cycloalkylgroup which may be substituted by a halogen or a C₁₋₄ alkoxy, or R^(db)and R^(dc) may bond with a nitrogen atom to form a cyclic amino groupand R^(dd) is a C₁₋₆ alkyl group or a C₃₋₈ cycloalkyl group), eachR^(d1) may be the same or different from each other when pd is two ormore, and each R^(d2), may be the same or different from each other whenqd is two or more, or the formula:R^(e1)—X^(e1)—W^(e)—X^(e2)-Z^(e1)-Z^(e2)—R^(e2)  (eI) wherein R^(e1)represents a 5 to 6-membered cyclic ring group which may be substituted,X^(e1) represents a bond or a bivalent group, in which the number ofatoms constituting the straight-chain portion is 1 to 4, W^(e)represents a bivalent group represented by formula:

wherein each of ring A^(e) and ring B^(e) represents a 5- to 7-memberedcyclic group which may be substituted, each of Ee₁ and Ee₄ is a carbonatom which may be substituted or a nitrogen atom which may besubstituted, each of Ee₂ and Ee₃ is a carbon atom which may besubstituted, a nitrogen atom which may be substituted, or a sulfur atomwhich may be oxidized or an oxygen atom, each of a^(e) and b^(e) is asingle bond or a double bond), X^(e2) is a bivalent group in which thenumber of atoms constituting the straight-chain portion is 1 to 4,Z^(e1) is a bond or a bivalent cyclic ring group, Z^(e2) is a bond or abivalent cyclic ring group in which the number of atoms constituting thestraight-chain portion is 1 to 4, and R^(e2) is (1) an amino group whichmay be substituted, and the nitrogen atom may be converted into aquaternary ammonium or an N-oxide, (2) a nitrogen-containingheterocyclic ring group which may be substituted, may contain sulfuratom or an oxygen atom as a ring-constituting atom, and the nitrogenatom may be converted into a quaternary ammonium or a N-oxide, (3) agroup which is bonded via the sulfur atom, (4) a group represented byformula:

wherein ek is 0 or 1, the phosphorus atom may form a phosphonium saltwhen ek is 0, and each of R^(e5′) and R^(e6′) is a hydrocarbon atomwhich may be substituted, a hydroxyl group which may be substituted, oran amino group which may be substituted, and R^(e5′) and R^(e6′) maybond to each other to form a cyclic ring group together with theadjacent phosphorus atom, (5) an amidino group which may be substitutedor (6) a guanidino group which may be substituted, or a salt thereof. 2.An agent for the prevention or treatment of chronic rheumatoidarthritis, autoimmune diseases, allergic disorders, ischemic brain celldamage, myocardial infarction, chronic nephritis, and arteriosclerosiswhich comprises a compound having a CCR antagonistic effect representedby the formula:

wherein R^(a1) is a hydrogen atom, a hydrocarbon group which may besubstituted, a non-aromatic heterocyclic group which may be substituted,R^(a2) is a hydrocarbon group which may be substituted, a non-aromaticheterocyclic group which may be substituted, or R^(a1) and R^(a2) maycombine with each other together with A^(a) to form a heterocyclic groupwhich may be substituted, A^(a) is N or N⁺—R^(a5).Y^(a−) (R^(a5) is ahydrocarbon group, Y^(a−) is a counter anion), R^(a3) is a cyclichydrocarbon group which may be substituted or a heterocyclic group whichmay be substituted, na is 0 or 1, R^(a4) is a hydrogen atom, ahydrocarbon group which may be substituted, a heterocyclic group whichmay be substituted, an alkoxy group which may be substituted, an aryloxygroup which may be substituted, or an amino group which may besubstituted, E^(a) is a divalent aliphatic hydrocarbon group which maybe substituted by a group other than an oxo group, G^(a1) is a bond, COor SO₂, G^(a2) is CO, SO₂, NHCO, CONH or OCO, J^(a) is methine or anitrogen atom, and each of Q^(a) and R^(a) is a bond or a divalent C₁₋₃aliphatic hydrocarbon which may be substituted, with the proviso thatJ^(a) is methine when G^(a2) is OCO, one of Q^(a) and R^(a) is not abond when the other is a bond, and each of Q^(a) and R^(a) is notsubstituted by an oxo group when G^(a1) is a bond, the formula:

wherein R^(b1) is a hydrocarbon group which may be substituted; R^(b2)is a cyclic hydrocarbon group which may be substituted or a heterocyclicgroup which may be substituted; R^(b3) is a halogen atom, a carbamoylgroup which may be substituted, a sulfamoyl group which may besubstituted, an acyl group derived from a sulfonic acid, a C₁₋₄ alkylgroup which may be substituted, a C₁₋₄ alkoxy group which may besubstituted, an amino group which may be substituted, a nitro group or acyano group; R^(b4) is a hydrogen atom or a hydroxy group; nb is aninteger of 0 or 1; pb is an integer of 0 or 1 to 4, the formula:

wherein R^(c1) is a hydrocarbon group, R^(c2) is a hydrocarbon grouphaving 2 or more carbon atoms, or R^(c1) and R^(c2) may be boundtogether with the adjacent nitrogen atom to form a ring which may have asubstituent or substituents, R^(c3) is a hydrocarbon group which mayhave a substituent or substituents or a heterocyclic group which mayhave a substituent or substituents, R^(c4) is a hydrogen atom, ahydrocarbon group which may have a substituent or substituents or aheterocyclic group which may have a substituent or substituents, E^(c)is a divalent aliphatic hydrocarbon group which may have a substituentor substituents other than an oxo group, G^(c) is CO or SO₂, J^(c) is anitrogen atom or a methine group which may have a substituent orsubstituents, and Q^(c) and R^(c) are each a bond or a divalentaliphatic C₁₋₃ hydrocarbon group which may have a substituent orsubstituents, the formula:

wherein A^(d) is a group represented by the formula:

wherein, R^(d3) is (1) a hydrocarbon group which may be substituted, (2)a C₁₋₄ alkoxy group which may be substituted or (3) an amino group whichmay be substituted; X^(d) is a bond, —SO₂— or —CO—; nd is an integer of1 to 3; md is 0 or an integer of 1 to 3; R^(d4) and R^(d5) are the sameor different and each of which is a hydrogen atom or a C₁₋₆ alkyl group;R^(d6) is a hydroxyl group, a C₁₋₆ alkyl group or a C₂₋₆ alkenyl group;rd is an integer of 2 to 4; B^(d) is a bond, —CH₂—, —SO₂—, —SO—, —S—,—O—, —CO—, —NR^(da)—SO₂— or —NR^(da)—CO— (wherein, R^(da) is a hydrogenatom, a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group or a C₃₋₈ cycloalkylgroup); each of pd and qd is 0 or an integer of 1 to 4; R^(d1) is ahalogen atom, a C₁₋₆ alkyl group, a C₂₋₄ alkenyl group, a C₁₋₄ alkanoylgroup, a C₁₋₄ alkoxy group, a cyano group, a trifloromethyl group, anitro group, a hydroxyl group, an amino group or an amidino group;R^(d2) is 1) a halogen, 2) a C₁₋₆ alkyl which may be substituted by ahalogen or a C₁₋₄ alkoxy, 3) a C₁₋₄ alkoxy which may be substituted by ahalogen or a C₁₋₄ alkoxy, 4) nitro, 5) cyano, 6) hydroxyl, 7) a C₁₋₄alkanoylamino, 8) SO₂NR^(db)R^(dc), 9) SO₂R^(dd), 10) CONR^(db)R^(dc),11) NR^(db)R^(dc) or 12) NR^(da)—SO₂R^(dd) (wherein, R^(da) has themeaning given above, and R^(db) and R^(dc) may be the same or different,and are (1) a hydrogen atom, (2) a C₁₋₆ alkyl group which may besubstituted by a halogen or a C₁₋₄ alkoxy, or (3) a C₃₋₈ cycloalkylgroup which may be substituted by a halogen or a C₁₋₄ alkoxy, or R^(db)and R^(dc) may bond with a nitrogen atom to form a cyclic amino groupand R^(dd) is a C₁₋₆ alkyl group or a C₃₋₈ cycloalkyl group), eachR^(d1) may be the same or different from each other when pd is two ormore, and each R^(d2), may be the same or different from each other whenqd is two or more, or the formula:R^(e1)—X^(e1)—W^(e)—X^(e2)-Z^(e1)-Z^(e2)—R^(e2)  (eI) wherein R^(e1)represents a 5 to 6-membered cyclic ring group which may be substituted,X^(e1) represents a bond or a bivalent group, in which the number ofatoms constituting the straight-chain portion is 1 to 4, W^(e)represents a bivalent group represented by formula:

wherein each of ring A^(e) and ring B^(e) represents a 5- to 7-memberedcyclic group which may be substituted, each of Ee₁ and Ee₄ is a carbonatom which may be substituted or a nitrogen atom which may besubstituted, each of Ee₂ and Ee₃ is a carbon atom which may besubstituted, a nitrogen atom which may be substituted, or a sulfur atomwhich may be oxidized or an oxygen atom, each of a^(e) and b^(e) is asingle bond or a double bond), X^(e2) is a bivalent group in which thenumber of atoms constituting the straight-chain portion is 1 to 4,Z^(e1) is a bond or a bivalent cyclic ring group, Z^(e2) is a bond or abivalent cyclic ring group in which the number of atoms constituting thestraight-chain portion is 1 to 4, and R^(e2) is (1) an amino group whichmay be substituted, and the nitrogen atom may be converted into aquaternary ammonium or an N-oxide, (2) a nitrogen-containingheterocyclic ring group which may be substituted, may contain sulfuratom or an oxygen atom as a ring-constituting atom, and the nitrogenatom may be converted into a quaternary ammonium or a N-oxide, (3) agroup which is bonded via the sulfur atom, (4) a group represented byformula:

wherein ek is 0 or 1, the phosphorus atom may form a phosphonium saltwhen ek is 0, and each of R^(e5′) and R^(e6′) is a hydrocarbon atomwhich may be substituted, a hydroxyl group which may be substituted, oran amino group which may be substituted, and R^(e5′) and R^(e6′) maybond to each other to form a cyclic ring group together with theadjacent phosphorus atom, (5) an amidino group which may be substitutedor (6) a guanidino group which may be substituted, or a salt thereof. 3.The agent for the prevention or treatment according to claim 1, whereinthe compound having a CCR antagonistic effect or a salt thereof isN-(3,4-dichlorophenyl)-1-(methylsulfonyl)-N-{3-[4-({4-[(methylsulfonyl)-amino]phenyl}sulfonyl)-1-piperidinyl]propyl}-4-piperidinecarboxamide,N-(3-chlorophenyl)-1-(methylsulfonyl)-N-(3-{4-[4-(methylsulfonyl)benzyl]-1-piperidinyl}propyl)-4-piperidinecarboxamide,N-(3-{4-[4-(aminocarbonyl)benzyl]-1-piperidinyl}propyl)-N-(3,4-dichlorophenyl)-1-(methylsulfonyl)-4-piperidinecarboxamide,1-acetyl-N-(3-{4-[4-(aminocarbonyl)benzyl]-1-piperidinyl}propyl)-N-(3-chloro-4-methylphenyl)-4-piperidinecarboxamide,N-(3,4-dichlorophenyl)-N-(3-{4-[4-(ethylsulfonyl)benzyl]-1-piperidinyl}propyl)-1-(methylsulfonyl)-4-piperidinecarboxamide,N-(3,4-dichlorophenyl)-N-(3-{4-[4-(isopropylsulfonyl)benzyl]-1-piperidinyl}propyl)-1-(methylsulfonyl)-4-piperidinecarboxamide,N-(3-chlorophenyl)-N-(3-{4-[4-(isopropylsulfonyl)benzyl]-1-piperidinyl}propyl)-1-(methylsulfonyl)-4-piperidinecarboxamide,N-(3-chlorophenyl)-N-(3-{4-[4-(ethylsulfonyl)benzyl]-1-piperidinyl}propyl)-1-(methylsulfonyl)-4-piperidinecarboxamide,N-(3,4-dichlorophenyl)-1-(methylsulfonyl)-N-(3-{4-[4-(methylsulfonyl)benzyl]-1-piperidinyl}propyl)-4-piperidinecarboxamide,N-(3-{4-[4-(aminocarbonyl)benzyl]-1-piperidinyl}propyl)-N-(3-chloro-4-methylphenyl)-1-(methylsulfonyl)-4-piperidinecarboxamide,N-[3-(4-benzyl-1-piperidinyl)propyl]-N′-(4-chlorophenyl)-N-phenylurea,N′-(4-chlorophenyl)-N-{3-[4-(4-fluorobenzyl)-1-piperidinyl]propyl}-N-phenylurea,N′-(4-chlorophenyl)-N-(3-{4-[4-(4-morpholinylsulfonyl)benzyl]-1-piperidinyl}propyl)-N-phenylurea,N′-(4-chlorophenyl)-N-(3-{4-[4-(4-methylsulfonyl)benzyl]-1-piperidinyl}propyl)-N-phenylurea,4-{[1-(3-{[(4-chloroanilino)carbonyl]anilino}propyl)-4-piperidinyl]methyl}benzamide,N-[3-(4-benzyl-1-piperidinyl)propyl]-N-(3,4-dichlorophenyl)-1-methyl-5-oxo-3-pyrrolidinecarboxamide,1-benzyl-N-[3-(4-benzyl-1-piperidinyl)propyl]-5-oxo-N-phenyl-3-pyrrolidinecarboxamide,N-[3-(4-benzyl-1-piperidinyl)propyl]-1-(2-chlorobenzyl)-5-oxo-N-phenyl-3-pyrrolidinecarboxamide,N-(3,4-dichlorophenyl)-N-{3-[4-(4-fluorobenzyl)-1-piperidinyl]propyl}-1-methyl-5-oxo-3-pyrrolidinecarboxamide,N-[3-(4-benzyl-1-piperidinyl)propyl]-5-oxo-N-phenyl-1-(2,2,2-trifluoroethyl)-3-pyrrolidinecarboxamide,N-(3,4-dichlorophenyl)-N-(3-{4-[4-(methylsulfonyl)benzyl]-1-piperidinyl}propyl)-2-[1-(methylsulfonyl)-4-piperidinyl]acetamide,N-(3,4-dichlorophenyl)-N-(3-{4-[4-(isopropylsulfonyl)benzyl]-1-piperidinyl}propyl)-2-[1-(methylsulfonyl)-4-piperidinyl]acetamide,3-(1-acetyl-4-piperidinyl)-N-(3,4-dichlorophenyl)-N-(3-{4-[4-(methylsulfonyl)benzyl]-1-piperidinyl}propyl)propanamide,orN-(3,4-dichlorophenyl)-4-hydroxy-1-(methylsulfonyl)-N-(3-{4-[4-(methylsulfonyl)benzyl]-1-piperidinyl}propyl)-4-piperidinecarboxamideor a salt thereof.
 4. The prevention or treatment agent according toclaim 1, wherein the compound having a CCR antagonistic effect or a saltthereof isN-methyl-N-[4-[[[2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]carbonyl]amino]benzyl]piperidiniumiodide,N-methyl-N-[4-[[[7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4-yl]carbonyl]amino]benzyl]piperidiniumiodide,N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4-carboxamide,N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-(4-morpholinophenyl)-2,3-dihydro-1-benzoxepin-4-carboxamide,7-(4-ethoxyphenyl)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-2,3-dihydro-1-benzoxepin-4-carboxamide,N,N-dimethyl-N-[4-[[[2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]carbonyl]amino]benzyl]-N-(tetrahydropyran-4-yl)ammoniumiodide,N-methyl-N-[4-[[[7-(4-methylphenyl)-3,4-dihydronaphthalen-2-yl]carbonyl]amino]benzyl]piperidiniumiodide,N,N-dimethyl-N-(4-(((2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl)carbonyl)amino)benzyl)-N-(4-tetrahydropyranyl)ammoniumchloride,N,N-dimethyl-N-(((7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4-yl)carbonyl)amino)benzyl)-N-(4-oxocyclohexyl)ammoniumchloride,N-(4-(((7-(4-ethoxyphenyl)-2,3-dihydro-1-benzoxepin-4-yl)carbonyl)amino)benzyl)-N,N-dimethyl-N-(4-tetrahydropyranyl)ammoniumchloride,N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-(4-propoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide,7-(4-butoxyphenyl)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide,7-[4-[N-methyl-N-(2-propoxyethyl)amino]phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide,7-[4-(2-ethoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide,N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-[4-(2-propoxyethoxy)phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide,7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide,7-[4-(2-ethoxyethoxy)-3,5-dimethylphenyl]-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide,7-[2-chloro-4-(2-propoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide,7-(3-methyl-4-propoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide,7-(3,4-dipropoxyphenyl)-N-(4-((N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino)methyl)phenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide,7-[4-(2-ethoxyethoxy)phenyl]-1-ethyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,1-ethyl-7-[4-(2-propoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,7-[4-(2-butoxyethoxy)phenyl]-1-ethyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,7-[4-(2-ethoxyethoxy)phenyl]-1-formyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,1-formyl-7-[4-(2-propoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,7-[4-(2-butoxyethoxy)phenyl]-1-formyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-5-yl)amino]methyl]phenyl]-1-propyl-2,3-dihydro-1-benzoazepin-4-carboxamide,N-[4-[[N-methyl-N-(tetrahydropyran-5-yl)amino]methyl]phenyl]-7-[4-(2-propoxyethoxy)phenyl]-1-propyl-2,3-dihydro-1-benzoazepin-4-carboxamide,1-benzyl-7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,7-[4-(2-butoxyethoxy)phenyl]-1-cyclopropylmethyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-phenyl-2,3-dihydro-1-benzoazepin-4-carboxamide,7-[4-(2-butoxyethoxy)phenyl]-1-(3,4-methylenedioxy)phenyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,7-[4-(2-butoxyethoxy)phenyl]-1-(2-methyloxazol-5-yl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,1-allyl-7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(3-thienyl)methyl-2,3-dihydro-1-benzoazepin-4-carboxamide,7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(thiazol-2-yl)methyl-2,3-dihydro-1-benzoazepin-4-carboxamide,7-[4-(2-butoxyethoxy)phenyl]-1-(1-methylpyrazol-4-yl)methyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,7-[4-(2-butoxyethoxy)phenyl]-1-(3-methylisothiazol-5-yl)methyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,7-[4-(2-butoxyethoxy)phenyl]-1-(1-ethylpyrazol-4-yl)methyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[N-methyl-N-(tetrahydropyran-5-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,1-isobutyl-N-[4-[[N-methyl-N-(tetrahydropyran-5-yl)amino]methyl]phenyl]-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(thiazol-5-yl)methyl-2,3-dihydro-1-benzoazepin-4-carboxamide,7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(1-methyltetrazol-5-yl)methyl-2,3-dihydro-1-benzoazepin-4-carboxamide,or7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(2-methyltetrazol-5-yl)methyl-2,3-dihydro-1-benzoazepin-4-carboxamideor a salt thereof.
 5. A method of preventing or treating graft-versushost disease and/or rejection reactions during organ or bone marrowtransplantation, which comprises the step of administering an effectiveamount of a compound having a CCR antagonist effect to a mammal.
 6. Amethod of preventing or treating chronic rheumatoid arthritis,autoimmune diseases, allergic disorders, ischemic brain cell damage,myocardial infarction, chronic nephritis, and arteriosclerosis, whichcomprises the step of administering an effective amount of a compoundhaving a CCR antagonist effect to a mammal.
 7. Use of a compound havinga CCR antagonist effect for manufacturing an agent for the prevention ortreatment of graft-versus host disease and/or rejection reactions duringorgan or bone marrow transplantation.
 8. Use of a compound having a CCRantagonist effect for manufacturing an agent for the prevention ortreatment of chronic rheumatoid arthritis, autoimmune diseases, allergicdisorders, ischemic brain cell damage, myocardial infarction, chronicnephritis, and arteriosclerosis.
 9. The agent for the prevention ortreatment according to claim 2, wherein the compound having a CCRantagonistic effect or a salt thereof isN-(3,4-dichlorophenyl)-1-(methylsulfonyl)-N-{3-[4-({4-[(methylsulfonyl)-amino]phenyl}sulfonyl)-1-piperidinyl]propyl}-4-piperidinecarboxamide,N-(3-chlorophenyl)-1-(methylsulfonyl)-N-(3-{4-[4-(methylsulfonyl)benzyl]-1-piperidinyl}propyl)-4-piperidinecarboxamide,N-(3-{4-[4-(aminocarbonyl)benzyl]-1-piperidinyl}propyl)-N-(3,4-dichlorophenyl)-1-(methylsulfonyl)-4-piperidinecarboxamide,1-acetyl-N-(3-{4-[4-(aminocarbonyl)benzyl]-1-piperidinyl}propyl)-N-(3-chloro-4-methylphenyl)-4-piperidinecarboxamide,N-(3,4-dichlorophenyl)-N-(3-{4-[4-(ethylsulfonyl)benzyl]-1-piperidinyl}propyl)-1-(methylsulfonyl)-4-piperidinecarboxamide,N-(3,4-dichlorophenyl)-N-(3-{4-[4-(isopropylsulfonyl)benzyl]-1-piperidinyl}propyl)-1-(methylsulfonyl)-4-piperidinecarboxamide,N-(3-chlorophenyl)-N-(3-{4-[4-(isopropylsulfonyl)benzyl]-1-piperidinyl}propyl)-1-(methylsulfonyl)-4-piperidinecarboxamide,N-(3-chlorophenyl)-N-(3-{4-[4-(ethylsulfonyl)benzyl]-1-piperidinyl}propyl)-1-(methylsulfonyl)-4-piperidinecarboxamide,N-(3,4-dichlorophenyl)-1-(methylsulfonyl)-N-(3-{4-[4-(methylsulfonyl)benzyl]-1-piperidinyl}propyl)-4-piperidinecarboxamide,N-(3-{4-[4-(aminocarbonyl)benzyl]-1-piperidinyl}propyl)-N-(3-chloro-4-methylphenyl)-1-(methylsulfonyl)-4-piperidinecarboxamide,N-[3-(4-benzyl-1-piperidinyl)propyl]-N′-(4-chlorophenyl)-N-phenylurea,N′-(4-chlorophenyl)-N-{3-[4-(4-fluorobenzyl)-1-piperidinyl]propyl}-N-phenylurea,N′-(4-chlorophenyl)-N-(3-{4-[4-(4-morpholinylsulfonyl)benzyl]-1-piperidinyl}propyl)-N-phenylurea,N′-(4-chlorophenyl)-N-(3-{4-[4-(4-methylsulfonyl)benzyl]-1-piperidinyl}propyl)-N-phenylurea,4-{[1-(3-{[(4-chloroanilino)carbonyl]anilino}propyl)-4-piperidinyl]methyl}benzamide,N-[3-(4-benzyl-1-piperidinyl)propyl]-N-(3,4-dichlorophenyl)-1-methyl-5-oxo-3-pyrrolidinecarboxamide,1-benzyl-N-[3-(4-benzyl-1-piperidinyl)propyl]-5-oxo-N-phenyl-3-pyrrolidinecarboxamide,N-[3-(4-benzyl-1-piperidinyl)propyl]-1-(2-chlorobenzyl)-5-oxo-N-phenyl-3-pyrrolidinecarboxamide,N-(3,4-dichlorophenyl)-N-{3-[4-(4-fluorobenzyl)-1-piperidinyl]propyl}-1-methyl-5-oxo-3-pyrrolidinecarboxamide,N-[3-(4-benzyl-1-piperidinyl)propyl]-5-oxo-N-phenyl-1-(2,2,2-trifluoroethyl)-3-pyrrolidinecarboxamide,N-(3,4-dichlorophenyl)-N-(3-{4-[4-(methylsulfonyl)benzyl]-1-piperidinyl}propyl)-2-[1-(methylsulfonyl)-4-piperidinyl]acetamide,N-(3,4-dichlorophenyl)-N-(3-{4-[4-(isopropylsulfonyl)benzyl]-1-piperidinyl}propyl)-2-[1-(methylsulfonyl)-4-piperidinyl]acetamide,3-(1-acetyl-4-piperidinyl)-N-(3,4-dichlorophenyl)-N-(3-{4-[4-(methylsulfonyl)benzyl]-1-piperidinyl}propyl)propanamide,orN-(3,4-dichlorophenyl)-4-hydroxy-1-(methylsulfonyl)-N-(3-{4-[4-(methylsulfonyl)benzyl]-1-piperidinyl}propyl)-4-piperidinecarboxamideor a salt thereof.
 10. The prevention or treatment agent according toclaim 2, wherein the compound having a CCR antagonistic effect or a saltthereof isN-methyl-N-[4-[[[2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]carbonyl]amino]benzyl]piperidiniumiodide,N-methyl-N-[4-[[[7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4-yl]carbonyl]amino]benzyl]piperidiniumiodide,N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4-carboxamide,N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-(4-morpholinophenyl)-2,3-dihydro-1-benzoxepin-4-carboxamide,7-(4-ethoxyphenyl)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-2,3-dihydro-1-benzoxepin-4-carboxamide,N,N-dimethyl-N-[4-[[[2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]carbonyl]amino]benzyl]-N-(tetrahydropyran-4-yl)ammoniumiodide,N-methyl-N-[4-[[[7-(4-methylphenyl)-3,4-dihydronaphthalen-2-yl]carbonyl]amino]benzyl]piperidiniumiodide,N,N-dimethyl-N-(4-(((2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl)carbonyl)amino)benzyl)-N-(4-tetrahydropyranyl)ammoniumchloride,N,N-dimethyl-N-(((7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4-yl)carbonyl)amino)benzyl)-N-(4-oxocyclohexyl)ammoniumchloride,N-(4-(((7-(4-ethoxyphenyl)-2,3-dihydro-1-benzoxepin-4-yl)carbonyl)amino)benzyl)-N,N-dimethyl-N-(4-tetrahydropyranyl)ammoniumchloride,N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-(4-propoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide,7-(4-butoxyphenyl)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide,7-[4-[N-methyl-N-(2-propoxyethyl)amino]phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide,7-[4-(2-ethoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide,N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-[4-(2-propoxyethoxy)phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide,7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide,7-[4-(2-ethoxyethoxy)-3,5-dimethylphenyl]-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide,7-[2-chloro-4-(2-propoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide,7-(3-methyl-4-propoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide,7-(3,4-dipropoxyphenyl)-N-(4-((N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino)methyl)phenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepin-4-carboxamide,7-[4-(2-ethoxyethoxy)phenyl]-1-ethyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,1-ethyl-7-[4-(2-propoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,7-[4-(2-butoxyethoxy)phenyl]-1-ethyl—N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,7-[4-(2-ethoxyethoxy)phenyl]-1-formyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,1-formyl-7-[4-(2-propoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,7-[4-(2-butoxyethoxy)phenyl]-1-formyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-5-yl)amino]methyl]phenyl]-1-propyl-2,3-dihydro-1-benzoazepin-4-carboxamide,N-[4-[[N-methyl-N-(tetrahydropyran-5-yl)amino]methyl]phenyl]-7-[4-(2-propoxyethoxy)phenyl]-1-propyl-2,3-dihydro-1-benzoazepin-4-carboxamide,1-benzyl-7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,7-[4-(2-butoxyethoxy)phenyl]-1-cyclopropylmethyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-phenyl-2,3-dihydro-1-benzoazepin-4-carboxamide,7-[4-(2-butoxyethoxy)phenyl]-1-(3,4-methylenedioxy)phenyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,7-[4-(2-butoxyethoxy)phenyl]-1-(2-methyloxazol-5-yl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,1-allyl-7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(3-thienyl)methyl-2,3-dihydro-1-benzoazepin-4-carboxamide,7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(thiazol-2-yl)methyl-2,3-dihydro-1-benzoazepin-4-carboxamide,7-[4-(2-butoxyethoxy)phenyl]-1-(1-methylpyrazol-4-yl)methyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,7-[4-(2-butoxyethoxy)phenyl]-1-(3-methylisothiazol-5-yl)methyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,7-[4-(2-butoxyethoxy)phenyl]-1-(1-ethylpyrazol-4-yl)methyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[N-methyl-N-(tetrahydropyran-5-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,1-isobutyl-N-[4-[[N-methyl-N-(tetrahydropyran-5-yl)amino]methyl]phenyl]-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1-benzoazepin-4-carboxamide,7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(thiazol-5-yl)methyl-2,3-dihydro-1-benzoazepin-4-carboxamide,7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(1-methyltetrazol-5-yl)methyl-2,3-dihydro-1-benzoazepin-4-carboxamide,or7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(2-methyltetrazol-5-yl)methyl-2,3-dihydro-1-benzoazepin-4-carboxamideor a salt thereof.